Pyrrole antifungal agents

ABSTRACT

The invention provides compounds of formula (I), and pharmaceutically and agriculturally acceptable salts thereof; wherein: R1, R2, R3, R4, R5, R6, A1, L1 and n are as defined herein. These compounds and their pharmaceutically acceptable salts are useful in prevention or treatment of a fungal disease. Compounds of formula (I), and agriculturally acceptable salts thereof, may also be used as agricultural fungicides.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Phase filing under 35 U.S.C. §371 ofInternational Application No. PCT/GB2009/01058, filed on Apr. 23, 2009,which claims priority to GB Patent Application No. 0807532.7, filed onApr. 24, 2008 and GB Patent Application No. 0819696.6, filed on Oct. 27,2008, the contents of which are incorporated herein by reference intheir entirety.

FIELD OF THE INVENTION

This invention relates to pyrrole compounds, combinations andcompositions comprising the pyrrole compounds and known antifungalagents, and their therapeutic use in prevention or treatment of fungaldiseases. It also relates to the use of the compounds, combinations andcompositions as agricultural fungicides.

BACKGROUND OF THE INVENTION

Invasive fungal infections are well recognised as diseases of theimmunocompromised host. Over the last twenty years there have beensignificant rises in the number of recorded instances of fungalinfection (Groll et al., 1996. J Infect 33, 23-32). In part this is dueto increased awareness and improved diagnosis of fungal infection.However, the primary cause of this increased incidence is the vast risein the number of susceptible individuals. This is due to a number offactors including new and aggressive immunosuppressive therapies,increased survival in intensive care, increased numbers of transplantprocedures and the greater use of antibiotics worldwide.

In certain patient groups, fungal infection occurs at high frequency;lung transplant recipients have a frequency of up to 20% colonisationand infection with a fungal organism and fungal infection in allogenichaemopoetic stem cell transplant recipients is as high as 15% (Ribaud etal., 1999, Clin Infect Dis. 28:322-30).

Currently only four classes of antifungal drug are available to treatsystemic fungal infections. These are the polyenes (e.g., amphotericinB), the azoles (e.g., ketoconazole or itraconazole), the echinocandins(e.g., caspofungin) and flucytosine.

The polyenes are the oldest class of antifungal agent being firstintroduced in the 1950's. The exact mode of action remains unclear butpolyenes are only effective against organisms that contain sterols intheir outer membranes. It has been proposed that amphotericin Binteracts with membrane sterols to produce pores allowing leakage ofcytoplasmic components and subsequent cell death.

Azoles work by inhibition of the 14α-demethylase via a cytochromeP450-dependent mechanism. This leads to a depletion of the membranesterol ergosterol and the accumulation of sterol precursors resulting ina plasma membrane with altered fluidity and structure.

Echinocandins work by the inhibition of the cell wall synthetic enzymeβ-glucan synthase. This leads to abnormal cell wall formation, osmoticsensitivity and cell lysis.

Flucytosine is a pyrimidine analogue interfering with cellularpyrimidine metabolism as well DNA, RNA and protein synthesis. Howeverwidespread resistance to flucyotosine limits its therapeutic use.

It can be seen that to date the currently available antifungal agentsact primarily against only two cellular targets; membrane sterols(polyenes and azoles) and β-glucan synthase (echinocandins).

Resistance to both azoles and polyenes has been widely reported leavingonly the recently introduced echinocandins to combat invasive fungalinfections. As the use of echinocandins increases, resistance by fungiwill inevitably occur.

The identification of new classes of antifungal agent is required togive the promise of positive therapeutic outcomes to patients.

SUMMARY OF THE INVENTION

The present inventors have found that certain pyrrole compounds, andcombinations of these pyrrole compounds with known antifungal agents,are antifungal. In particular, the compounds inhibit the growth of humanpathogenic fungi such as Aspergillus and therefore may be used to treatfungal infection and disease.

Accordingly, the present invention provides a pyrrole derivative offormula (I) or a pharmaceutically acceptable salt thereof for use in theprevention or treatment of a fungal disease:

wherein:

R1 represents hydrogen, unsubstituted or substituted C1-C8 alkyl, C2-C8alkenyl, C2-C8 alkynyl, —COR′ or —SO₂(C1-C4 alkyl), or a group -A2,-L2-A2, -L3-A2, -A2-L3-A3 or -A4;

A1 represents a bond, a C3-C6 cycloalkyl or an unsubstituted orsubstituted C6-C10 aryl or 5- to 12-membered heterocyclyl group;

A2 and A3 are the same or different and represent C3-C6 cycloalkyl or anunsubstituted or substituted C6-C10 aryl or 5- to 12-memberedheterocyclyl group;

A4 is an unsubstituted or substituted 5- to 12-membered heterocyclylgroup wherein 1 or 2 ring carbon atoms are replaced with a groupselected from >C(═O), >S(═O)₂, >C(═NOR7) where R7 is hydrogen or a C1-C4alkyl group, >C═CH₂ or >C(—OCH₂CH₂O—);

L1 represents a bond, a C1-C6 alkylene group in which none, one, two orthree —CH₂— groups are independently replaced by —O—, —S— or —NR′—, or a5- to 12-membered heterocyclyl group;

L2 represents —NR′—, —O—, —CO—, —OCO—, —OCONR′R″—, —CONR′R″— or —SO₂—;

L3 represents a bond or a C1-C4 alkylene group in which none, one or two—CH₂— groups are independently replaced by —O—, —S— or —NR′—;

n is 1 or 2;

R6 represents hydrogen or C1-C4 alkyl;

R5 represents an unsubstituted or substituted group selected from C6-C10aryl, a 5- to 12-membered heterocyclyl group, C1-C8 alkyl and C3-C6cycloalkyl, hydrogen, halogen or a group of formula —B1-B2 or —B3;

B1 represents an unsubstituted or substituted C6-C10 aryl group;

B2 represents an unsubstituted or substituted C6-C10 aryl or 5- to12-membered heterocyclyl group;

B3 is an unsubstituted or substituted 5- to 12-membered heterocyclylgroup where 1 or 2 ring carbon atoms are replaced with a group selectedfrom >C(═O), >S(═O)₂, >C(═NOR11) where R11 is hydrogen or a C1-C4 alkylgroup, >C═CH₂ or >C(—OCH₂CH₂O—);

R2 and R3 independently represent C6-C10 aryl, a 5- to 12-memberedheterocyclyl group, C3-C6 cycloalkyl, hydrogen, halogen, C1-C8 alkyl,C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, —OR′, —SR′, —SOR′,—SO₂R′, —SO₂NR′R″, —SO₃H, NR′R″, —NR′COR′, —CO₂R′, —CONR′R″, —COR′,—OCOR′, —CF₃, —NSO₂R′ or —OCONR′R″, or a group (C1-4) alkyl-A5, whereinnone, one or two —CH₂— groups are independently replaced by —O—, —S— or—NR′— and wherein A5 represents C6-10 aryl or a 5- to 12-memberedheterocyclyl group; or R2 and R3 together with the ring atoms to whichthey are bonded form a 5- to 7-membered, at least partially saturatedring containing a nitrogen atom from the adjacent pyrrole ring, andoptionally one or two further heteroatoms selected from N, O and S, withthe proviso that R2 and R3 do not form, together with the pyrrole ringto which they are bonded, an indolizine or tetrahydroindolizine ring;

R4 represents hydrogen, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8alkynyl, —OR′, —CO₂R′, —CONR′R″, —COR′, —CN, —NO₂, —NR′R″, CF₃, —Y—Z,C6-C10 aryl, or 5- to 12-membered heterocyclyl group, or a group offormula -Alk⁶-L5-A12, where Alk⁶ is a C1-C4 alkylene group, L5 is agroup of formula —C(═O)— or —NR13-C(═O)— and R13 is hydrogen or C1-C4alkyl, and A12 is an unsubstituted or substituted C6-C10 aryl or 5- to12-membered heterocyclyl group;

Y represents C1-C8 alkylene, C2-C8 alkenylene or C2-C8 alkynylene;

Z represents halogen, C3-C6 cycloalkyl, —OR′, —SR′, —SOR′, —SO₂R′,—SO₂NR′R″, —SO₃H, —NR′R″, —NR′COR′, —NO₂, —CO₂R′, —CONR′R″, —COR′,—OCOR′, —CN, —CF₃, —NSO₂R′, —OCONR′R″ or —CR′═NOR″; and R′ and R″independently represent hydrogen, C1-C8 alkyl, C2-C8 alkenyl or C2-C8alkynyl.

Preferably A1 represents a C3-C6 cycloalkyl or an unsubstituted orsubstituted C6-C10 aryl or 5- to 12-membered heterocyclyl group.

The present inventors have further found that a number of the compoundsof formula (I) have particular activity in inhibiting the growth of awide variety of fungi such as those of the Aspergillus and Candidagenera. The present invention accordingly also provides a pyrrolederivative of formula (IB) or a pharmaceutically acceptable salt thereoffor use in the prevention or treatment of a fungal disease:

wherein A1, L1, n, R1 and R3 to R5 are as defined for formula (I) above,and R2 is a group of formula -Alk₁-X—R′, wherein Alk₁ is anunsubstituted or substituted C1-C6 alkylene group, X is a group —O—,—S—, —NR″—, —CO₂—, —CONR″—, —OCO—, —OCONR″— or —SO₂—, and R′ and R″ areindependently selected from hydrogen and unsubstituted or substitutedC1-C4 alkyl.

The invention also provides the use of a derivative or pharmaceuticallyacceptable salt of formula (I) or (IB) as defined above for themanufacture of a medicament for the prevention or treatment of a fungaldisease. The invention also provides an agent for the treatment of afungal disease comprising a derivative or pharmaceutically acceptablesalt of formula (I) or (IB) as defined above. There is further provideda method of treating a subject suffering from or susceptible to a fungaldisease, which method comprises administering to said subject aneffective amount of a derivative or pharmaceutically acceptable salt offormula (I) or (IB) as defined above.

The invention also provides a method of controlling a fungal disease ina plant, which method comprises applying to the locus of the plant aderivative of formula (I) or (IB) as defined above or an agriculturallyacceptable salt thereof, optionally in combination with a secondantifungal agent. The invention also provides the use of a derivative offormula (I) or (IB) as defined above or an agriculturally acceptablesalt thereof, optionally in combination with a second antifungal agent,as an agricultural fungicide.

The invention also provides a pharmaceutical combination comprising acombination of a pyrrole derivative of formula (I) or (IB) or apharmaceutically acceptable salt thereof with a second antifungal agent.Also provided is a pharmaceutical composition comprising a combinationof a pyrrole derivative of formula (I) or (IB) or a pharmaceuticallyacceptable salt thereof with a second antifungal agent.

In the combinations of the invention the pyrrole derivative of formula(I) or (IB) or pharmaceutically acceptable salt thereof has anantifungal effect and is sometimes referred to as the “first antifungalagent”, to distinguish it from the second antifungal agent describedlater. In the combinations, compositions and products of the invention,the first antifungal agent is different from the second antifungalagent.

In the combination therapies of the invention, preferably the pyrrolederivative of formula (I) or (IB) or pharmaceutically acceptable saltthereof and the second antifungal agent are formulated for simultaneousor successive administration. Preferably the combination of the pyrrolederivative of formula (I) or (IB) or pharmaceutically acceptable saltthereof and the second antifungal agent are for use in the treatment orprevention of a fungal disease.

The invention further provides a product comprising a pyrrole derivativeof formula (I) or (IB) or a pharmaceutically acceptable salt thereof anda second antifungal agent for separate, simultaneous or sequential usein the prevention or treatment of a fungal disease.

There is also provided a pharmaceutical composition comprising (i) apyrrole of formula (I) or (IB) or a pharmaceutically acceptable saltthereof, (ii) a second antifungal agent, and (iii) a pharmaceuticallyacceptable carrier or diluent. Preferably the pharmaceutical compositionis for use in the treatment or prevention of a fungal disease.

The invention also provides the use of a pyrrole derivative of formula(I) or (IB) or a pharmaceutically acceptable salt thereof and a secondantifungal agent in the manufacture of a medicament for use in thetreatment or prevention of fungal disease. The invention also providesthe use of a pyrrole derivative of formula (I) or (IB) or apharmaceutically acceptable salt thereof in the manufacture of amedicament for administration with a second antifungal agent in thetreatment or prevention of fungal disease. Alternatively the inventionprovides the use of an antifungal agent (corresponding to the secondantifungal agent mentioned above) in the manufacture of a medicament foradministration with a pyrrole derivative of formula (I) or (IB) or apharmaceutically acceptable salt thereof in the treatment or preventionof fungal disease.

There is also disclosed a method of treating a fungal disease whichcomprises administering a therapeutically effective amount of a firstantifungal agent which is a pyrrole derivative of formula (I) or (IB) ora pharmaceutically acceptable salt thereof and a second antifungalagent. Furthermore, the invention relates to a kit comprising, inadmixture or in separate containers, a pyrrole derivative of formula (I)or (IB) or a pharmaceutically acceptable salt thereof and a secondantifungal agent.

The invention also provides a compound, which is a pyrrole derivative offormula (I) or a pharmaceutically acceptable salt thereof, for use in amethod of treatment of a human or animal body by therapy. In thisembodiment, R6 is hydrogen; A1 is a bond, a C3-C6 cycloalkyl or anunsubstituted or substituted C6-C10 aryl, 5- or 6-membered heterocyclylor 8- to 10-membered bicyclic heterocyclyl group; R2 is as defined abovewith the exception that when R2 is cycloalkyl it is an unsubstitutedcycloalkyl group; R4 represents hydrogen, halogen, C1-C8 alkyl, C2-C8alkenyl, C2-C8 alkynyl, —OR′, —CONR′R″, —COR′, —CN, —NO₂, —NR′R″, CF₃,—Y—Z, C6-C10 aryl, or 5- to 12-membered heterocyclyl group, or a groupof formula -Alk⁶-L5-A12, where Alk⁶ is a C1-C4 alkylene group, L5 is agroup of formula —O—C(═O)—, —C(═O)— or —NR13-C(═O)— and R13 is hydrogenor C1-C4 alkyl, Alt is an unsubstituted or substituted C6-C10 aryl or 5-to 12-membered heterocyclyl group and R′, R″, Y and Z are as definedabove; with the provisos that (i) when A1 is a bond, -L1-R1 is nothydrogen, (ii) when A1 is a bond, R2 is unsubstituted or substitutedphenyl and R3 to R5 are all hydrogen, -L1-R1 is not unsubstituted orsubstituted benzyl or substituted phenethyl, (iii) when A1 is a bond, R6is hydrogen and R3 to R5 are all hydrogen or chlorine, then none of L1,L3 and L1-R1 represents an unsubstituted or substituted C1-C4 alkylgroup; and (iv) the compound is not:

-   N-[1-(4-methyl-3-penten-1-yl)-4-piperidinyl]-1H-pyrrole-2-acetamide,-   5-Thia-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,    3-(hydroxymethyl)-8-oxo-7-[2-(2-pyrrolyl)glyoxylamido]-, acetate    ester,-   2-Oxo-N-[2-(5-piperidin-1-ylmethyl-1H-pyrrol-2-yl)-ethyl]-2-[5-(1H-pyrrol-2-ylmethyl)-1H-pyrrol-2-yl]-acetamide,-   2-oxo-N-[2-(1H-pyrrol-2-yl)-ethyl]-2-[5-(1H-pyrrol-2-ylmethyl)-1H-pyrrol-2-yl]-acetamide,-   5-Aminooxalyl-3-(2-methoxycarbonyl-ethyl)-4-methoxycarbonylmethyl-1H-pyrrole-2-carboxylic    acid tert-butyl ester,-   (2S,5R,6R)-3,3-Dimethyl-6-[2-(1-methyl-1H-pyrrol-2-yl)-2-oxo-acetylamino]-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylic    acid,-   (2S,5R,6R)-3,3-Dimethyl-7-oxo-6-[2-oxo-2-(1-phenyl-1H-pyrrol-2-yl)-acetylamino]-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylic    acid,-   (2S,5R,6R)-3,3-Dimethyl-7-oxo-6-[2-oxo-2-(1H-pyrrol-2-yl)-acetylamino]-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylic    acid,-   Potassium;    (2S,5R,6R)-3,3-dimethyl-7-oxo-6-[2-oxo-2-(1-phenyl-1H-pyrrol-2-yl)-acetylamino]-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate,-   Potassium;    (2S,5R,6R)-3,3-dimethyl-7-oxo-6-[2-oxo-2-(1H-pyrrol-2-yl)-acetylamino]-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate,    or-   Potassium;    (2S,5R,6R)-3,3-dimethyl-6-[2-(1-methyl-1H-pyrrol-2-yl)-2-oxo-acetylamino]-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate.

The invention also provides a compound, which is a pyrrole derivative offormula (I) or a pharmaceutically or agriculturally acceptable saltthereof:

wherein R1, L1, n, R3 and R5 are as defined above;

A1 is a bond, a C3-C6 cycloalkyl or an unsubstituted or substitutedC6-C10 aryl, 5- or 6-membered heterocyclyl or 8- to 10-membered bicyclicheterocyclyl group;

R6 represents hydrogen;

R2 represents C6-C10 aryl, a 5- to 12-membered heterocyclyl group otherthan benzothiophene, unsubstituted C3-C6 cycloalkyl, hydrogen, halogen,C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, —OR′, —SR′,—SOR′, —SO₂R′, —SO₂NR′R″, —SO₃H, —NR′R″, —NR′COR′, —CO₂R′, —CONR′R″,—COR′, —OCOR′, —CF₃, —NSO₂R′ or —OCONR′R″, or a group (C1-4) alkyl-A5,wherein none, one or two —CH₂— groups are independently replaced by —O—,—S— or —NR′— and wherein A5 represents C6-10 aryl or a 5- to 12-memberedheterocyclyl group; or R2 together with R3 and the ring atoms to whichthey are bonded form a 5- to 7-membered, at least partially saturatedring containing a nitrogen atom from the adjacent pyrrole ring, andoptionally one or two further heteroatoms selected from N, O and S, withthe proviso that R2 and R3 do not form, together with the pyrrole ringto which they are bonded, an indolizine or tetrahydroindolizine ring;

wherein when R2 represents aryl or heterocyclyl it is unsubstituted orsubstituted with one or more unsubstituted substituents selected fromhalogen, —NR′R″, —CO₂R′, —CONR′R″, —OCONR′R″, —OCOR′, —COCF₃ andhydroxyl, or C1-C6 alkyl or C1-C4 alkoxy which are unsubstituted orsubstituted with a hydroxyl or unsubstituted C1-C4 alkoxy group; whereinR′ and R″ are independently selected from hydrogen, unsubstituted C1-C4alkyl and C1-C4 alkyl substituted with a hydroxyl or unsubstituted C1-C4alkoxy group;

R4 represents hydrogen, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8alkynyl, —OR′, —CO₂R′, —CONR′R″, —CN, —NO₂, —NR′R″, CF₃, —Y—Z, C6-C10aryl, or 5- to 12-membered heterocyclyl group, or a group of formula-Alk⁶-L5-A12, where Alk⁶ is a C1-C4 alkylene group, L5 is a group offormula —O—C(═O)—, —C(═O)— or —NR13-C(═O)— and R13 is hydrogen or C1-C4alkyl, and A12 is an unsubstituted or substituted C6-C10 aryl or 5- to12-membered heterocyclyl group;

wherein Y, Z and, unless otherwise specified, R′ and R″ are as definedabove;

with the provisos that

-   -   when A1 is a bond, L1-R1 is not hydrogen;    -   when A1 is a bond, R2 is unsubstituted or substituted phenyl and        R3 to R5 are all hydrogen, -L1-R1 is not unsubstituted or        substituted benzyl or substituted phenethyl;    -   when A1 is a bond, R2 is hydrogen and R3 to R5 are all hydrogen        or chlorine, then none of L1, L3 and L1-R1 represents an        unsubstituted or substituted C1-C4 alkyl group; and    -   the compound is not

-   N-(4-Bromo-phenyl)-2-[1-(2-chloro-4-nitro-phenyl)-1H-pyrrol-2-yl]-2-oxo-acetamide,

-   2-[1-(2-chloro-4-nitro-phenyl)-1H-pyrrol-2-yl-N-(4-chloro-phenyl)-2-oxo-acetamide,

-   3-[2-(4-Fluoro-phenylaminooxalyl)-pyrrol-1-yl]-propionic acid,

-   N-Benzo[1,3]dioxol-5-yl-2-[1-(2-cyano-ethyl)-1H-pyrrol-2-yl]-2-oxo-acetamide,

-   2-[1-(2-Cyano-ethyl)-1H-pyrrol-2-yl]-N-(4-fluoro-phenyl)-2-oxo-acetamide,

-   N-(2,4-Difluoro-phenyl)-2-(1-methyl-1H-pyrrol-2-yl)-2-oxo-acetamide,

-   N-(2,3-Difluoro-phenyl)-2-(1-methyl-1H-pyrrol-2-yl)-2-oxo-acetamide,

-   2-(1-Methyl-1H-pyrrol-2-yl)-2-oxo-N-(4-phenoxy-phenyl)-acetamide,

-   N-(2-Methoxy-4-nitro-phenyl)-2-(1-methyl-1H-pyrrol-2-yl)-2-oxo-acetamide,

-   N-(2,3-Dichloro-phenyl)-2-(1-methyl-1H-pyrrol-2-yl)-2-oxo-acetamide,

-   4-[2-(1-Methyl-1H-pyrrol-2-yl)-2-oxo-acetylamino]-benzoic acid    methyl ester,

-   2-(1-Methyl-1H-pyrrol-2-yl)-2-oxo-N-(2-trifluoromethyl-phenyl)-acetamide,

-   2-(1-Methyl-1H-pyrrol-2-yl)-2-oxo-N-(3-trifluoromethyl-phenyl)-acetamide,

-   N-(3,5-Dichloro-phenyl)-2-(1-methyl-1H-pyrrol-2-yl)-2-oxo-acetamide,

-   N-(2,4-Dichloro-phenyl)-2-(1-methyl-1H-pyrrol-2-yl)-2-oxo-acetamide,

-   2-(1-Methyl-1H-pyrrol-2-yl)-2-oxo-N-phenyl-acetamide,

-   N-(4-Chloro-phenyl)-2-(1-methyl-1H-pyrrol-2-yl)-2-oxo-acetamide,

-   3-[2-(4-Bromo-phenylaminooxalyl)-pyrrol-1-yl]-thiophene-2-carboxylic    acid methyl ester,

-   3-[2-(4-Chloro-phenylaminooxalyl)-pyrrol-1-yl]-thiophene-2-carboxylic    acid methyl ester,

-   3-[2-(2-trifluoromethyl-phenylaminooxalyl)-pyrrol-1-yl]-thiophene-2-carboxylic    acid methyl ester,

-   3-[2-(4-trifluoromethyl-phenylaminooxalyl)-pyrrol-1-yl]-thiophene-2-carboxylic    acid methyl ester,

-   3-[2-(3-trifluoromethyl-phenylaminooxalyl)-pyrrol-1-yl]-thiophene-2-carboxylic    acid methyl ester,

-   3-[2-(4-Fluoro-phenylaminooxalyl)-pyrrol-1-yl]-thiophene-2-carboxylic    acid methyl ester,

-   N-[1-(4-methyl-3-penten-1-yl)-4-piperidinyl]-1H-pyrrole-2-acetamide,

-   3-(2-Allylaminooxalyl-pyrrol-1-yl)-thiophene-2-carboxylic acid    methyl ester,

-   3-(2-Propylaminooxalyl-pyrrol-1-yl)-thiophene-2-carboxylic acid    methyl ester,

-   5-Thia-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,    3-(hydroxymethyl)-8-oxo-7-[2-(2-pyrrolyl)glyoxylamido]-, acetate    ester

-   3-{2-[2-(3,4-Dimethoxy-phenyl)-ethylaminooxalyl]-pyrrol-1-yl}-propionic    acid

-   2-[1-(2-Cyano-ethyl)-1H-pyrrol-2-yl]-N-furan-2-ylmethyl-2-oxo-acetamide

-   2-[1-(2-Cyano-ethyl)-1H-pyrrol-2-yl]-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-2-oxo-acetamide

-   2-Oxo-N-[2-(5-piperidin-1-ylmethyl-1H-pyrrol-2-yl)-ethyl]-2-[5-(1H-pyrrol-2-ylmethyl)-1H-pyrrol-2-yl]-acetamide

-   2-oxo-N-[2-(1H-pyrrol-2-yl)-ethyl]-2-[5-(1H-pyrrol-2-ylmethyl)-1H-pyrrol-2-yl]-acetamide

-   5-Aminooxalyl-3-(2-methoxycarbonyl-ethyl)-4-methoxycarbonylmethyl-1H-pyrrole-2-carboxylic    acid tert-butyl ester

-   N-(3-Nitro-biphenyl-4-yl)-2-oxo-2-(1H-pyrrol-2-yl)-acetamide

-   (2S,5R,6R)-3,3-Dimethyl-6-[2-(1-methyl-1H-pyrrol-2-yl)-2-oxo-acetylamino]-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylic    acid

-   (2S,5R,6R)-3,3-Dimethyl-7-oxo-6-[2-oxo-2-(1-phenyl-1H-pyrrol-2-yl)-acetylamino]-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylic    acid

-   (2S,5R,6R)-3,3-Dimethyl-7-oxo-6-[2-oxo-2-(1H-pyrrol-2-yl)-acetylamino]-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylic    acid

-   Potassium;    (2S,5R,6R)-3,3-dimethyl-7-oxo-6-[2-oxo-2-(1-phenyl-1H-pyrrol-2-yl)-acetylamino]-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate

-   Potassium;    (2S,5R,6R)-3,3-dimethyl-7-oxo-6-[2-oxo-2-(1H-pyrrol-2-yl)-acetylamino]-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate    or

-   Potassium;    (2S,5R,6R)-3,3-dimethyl-6-[2-(1-methyl-1H-pyrrol-2-yl)-2-oxo-acetylamino]-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate.

The invention also provides a compound of formula (IB) as defined aboveor a pharmaceutically or agriculturally acceptable salt thereof,provided that the compound is not3-[2-(4-fluoro-phenylaminooxalyl)-pyrrol-1-yl]-propionic acid or3-{2-[2-(3,4-Dimethoxy-phenyl)-ethylaminooxalyl]-pyrrol-1-yl}-propionicacid.

Pharmaceutical compositions comprising a compound of the invention and apharmaceutically acceptable carrier or diluent, optionally together witha second antifungal agent, are also provided. Compositions comprising acompound of the invention and an agriculturally acceptable carrier ordiluent, optionally together with a second antifungal agent, are alsoprovided.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, a C1-C8 alkyl group or moiety can be linear, branched orcyclic but is preferably linear. It is preferably a C1-C6 alkyl group,more preferably a C1-C4 alkyl group, most preferably a C1-C3 alkylgroup. Suitable such alkyl groups and moieties include methyl, ethyl,n-propyl, i-propyl, n-butyl, sec-butyl and tert-butyl, as well aspentyl, e.g. CH₂C(CH₃)₃, hexyl, heptyl and octyl and isomers thereof. Asused herein, a C1-C8 alkylene group or moiety is a divalent alkyl groupor moiety as defined above, for example a C1-C4 alkylene group or moietysuch as methylene, ethylene or propylene.

As used herein, a C2-C8 alkenyl group or moiety can be linear, branchedor cyclic but is preferably linear. It contains one or morecarbon-carbon double bonds. It is preferably a C2-C6 alkenyl group, morepreferably a C2-C4 alkenyl group, most preferably a C2-C3 alkenyl group.Suitable such alkenyl groups and moieties include vinyl, allyl,propenyl, butenyl, e.g. CH₂C(Me)=CH₂, pentenyl, hexenyl, heptenyl andoctenyl and isomers thereof.

As used herein, a C2-C8 alkynyl group or moiety can be linear orbranched but is preferably linear. It contains one or more carbon-carbontriple bonds. It is preferably a C2-C6 alkynyl group, more preferably aC2-C4 alkynyl group, most preferably a C2-C3 alkynyl group. Suitablesuch alkynyl groups and moieties include ethynyl, propynyl, butynyl,pentynyl, hexynyl, heptynyl and octynyl and isomers thereof.

An alkyl, alkenyl or alkynyl group or moiety can be substituted orunsubstituted. Typically, it carries up to three substituents, e.g. oneor two substituents. Suitable substituents are preferably themselvesunsubstituted and include halogen such as fluorine, hydroxy, amino,(C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, C1-C4 alkoxy such as methoxy,ethoxy and propoxy, —S(C1-C4 alkyl) such as —SMe, —CO₂H, —CO₂(C1-C4alkyl), phenyl, 5- or 6-membered heterocyclyl such as pyridinyl,—CONR′R″ and —NR′CO(C1-C4 alkyl) where R′ and R″ are the same ordifferent and represent hydrogen or unsubstituted C1-C4 alkyl.Preferably R′ and R″ are the same or different and represent hydrogen ormethyl. More preferably R′ represents hydrogen and R″ represents methyl.Examples of these substituents include unsubstituted substituents suchas halogen (for example fluorine), hydroxy, amino, —S(C1-C4 alkyl) (forexample —SMe), phenyl, pyridinyl, —COO(C1-C4 alkyl) (for example —COOMe,—COOEt and —COOPr), —CONR′R″ (for example —CONHMe), —NR′CO(C1-C4 alkyl)(for example —NHCOMe), (C1-C4 alkyl)amino and di(C1-C4 alkyl)amino, andC1-C4 alkoxy such as methoxy, ethoxy or propoxy which are themselvesunsubstituted or further substituted with unsubstituted methoxy orethoxy. C1-C4 alkoxy, such as methoxy or ethoxy, halogen, such asfluorine, and hydroxy are preferred. Other preferred groups includeunsubstituted phenyl or pyridinyl, —NMe₂, —COOR′ where R′ is C1-C3alkyl, —CONHMe and —NHCOMe.

In a preferred embodiment, suitable substituents on an alkyl, alkenyl oralkynyl group or moiety are preferably themselves unsubstituted andinclude halogen such as fluorine, hydroxy, amino, (C1-C4 alkyl)amino,di(C1-C4 alkyl)amino, C1-C4 alkoxy such as methoxy or ethoxy, —CO₂H and—CO₂(C1-C4 alkyl). Preferred examples of these substituents includeunsubstituted substituents such as halogen (for example fluorine),hydroxy, amino, (C1-C4 alkyl)amino and di(C1-C4 alkyl)amino, and C1-C4alkoxy such as methoxy or ethoxy which are themselves unsubstituted orfurther substituted with unsubstituted methoxy or ethoxy. Most preferredare C1-C4 alkoxy, such as methoxy or ethoxy, halogen, such as fluorine,and hydroxy.

As used herein, a C3-C6 cycloalkyl group is typically a C4, C5 or C6cycloalkyl group, more preferably a C5 or C6 cycloalkyl group. Typicallya cycloalkyl group is unsubstituted or substituted with up to threesubstituents, e.g. one or two substituents. Suitable substituentsinclude C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Z and —Y—Z wherein Yand Z are as hereinbefore defined. Where present, preferably thesubstituents are themselves unsubstituted. Typically, a cycloalkyl groupis unsubstituted.

When Y is C1-C8 alkylene, it is preferably C1-C4 alkylene, morepreferably methylene or ethylene.

When Y is C2-C8 alkenylene, it is preferably C2-C4 alkenylene, morepreferably ethenylene.

When Y is C2-C8 alkynylene, it is preferably C2-C4 alkynylene, morepreferably ethynylene.

When R′ or R″ is C1-C8 alkyl, it is preferably C1-C4 alkyl, morepreferably methyl or ethyl.

When R′ or R″ is C2-C8 alkenyl, it is preferably C2-C4 alkenyl, morepreferably ethenyl.

When R′ or R″ is C2-C8 alkynyl, it is preferably C2-C4 alkynyl, morepreferably ethynyl.

As used herein, an aryl group or moiety is typically phenyl or naphthyl,more preferably phenyl.

As used herein and unless otherwise stated, a heterocyclyl group ormoiety is a saturated or unsaturated, 5- to 12-membered ring system inwhich the ring contains at least one heteroatom. Typically, the ringcontains up to three or four heteroatoms, e.g. one or two heteroatoms,selected from O, S and N. Thus, a heterocyclyl group or moiety istypically a 5- to 12-membered ring containing one, two or threeheteroatoms selected from O, S and N. Suitable such heterocyclyl groupsand moieties include, for example, monocyclic saturated 5- to 8-memberedrings, more preferably 5- to 7-membered rings, such astetrahydrofuranyl, piperidinyl, oxazolidinyl, morpholinyl,thiomorpholinyl, pyrrolidinyl, dioxolanyl, piperidonyl, azepanyl,piperazinyl, tetrahydropyranyl and 1,4-diazepanyl, more preferablypyrrolidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, piperidinyl,azepanyl and 1,4-diazepanyl, more preferably still more preferablypyrrolidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, piperidinyl,azepanyl and 1,4-diazepanyl; monocyclic at least partially unsaturated5- to 8-membered rings, more preferably 5- to 6-membered rings, such asfuranyl, pyrrolyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl and di- and tetrahydropyridinyl, e.g. oxazolyl,isoxazolyl, imidazolyl, furanyl, thiophenyl, pyrimidinyl or pyridinyl;bicyclic 8- to 10-membered ring systems such as indolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, benzoxazolyl, benzopyrazolyl,benzothiazolyl, benzotriazolyl, quinolinyl, quinazolinyl (includingisomers thereof, e.g. isoquinolinyl), quinoxalinyl, cinnolinyl, purinyland cyclopentapyridines which may optionally be partially unsaturated,for example dihydroindolyl; and tricyclic 11- or 12-membered ringsystems such as acridinyl, pteridinyl and benzathiazinyl. Particularexamples of such heterocyclyl groups and moieties include monocyclicsaturated 5- to 8-membered rings, more preferably monocyclic saturated5- to 7-membered rings such as pyrrolidinyl, morpholinyl, piperazinyl,tetrahydropyranyl, piperidinyl and 1,4-diazepanyl; and monocyclic atleast partially unsaturated 5- to 8-membered rings, more preferablymonocyclic unsaturated 5- to 6-membered rings such as oxazolyl,isoxazolyl, imidazolyl, furanyl, thiophenyl, pyrimidinyl or pyridinyl.Particular examples of bicyclic 8- to 10-membered ring systems includeindolyl, benzofuranyl, quinolinyl and isoquinolinyl, for examplebenzofuranyl, quinolinyl and isoquinolinyl.

A heterocyclyl or aryl group or moiety may be substituted orunsubstituted. Each ring atom may be unsubstituted or may carry one ortwo substituents. If desired, a nitrogen atom may be disubstituted and asulphur atom may be substituted, providing a charged heteroatom.Typically, a heterocyclyl or aryl group or moiety carries up to threesubstituents, e.g. one or two substituents. The heterocycle may beconnected to the remainder of the molecule by a bond to any of itsavailable ring positions.

Suitable substituents include C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl,Z and —Y—Z wherein Y and Z are as hereinbefore defined. Preferredsubstituents on an aryl or heterocyclyl group or moiety areunsubstituted substituents selected from halogen, —CO₂R′, —CONR′R″,OCOR′, hydroxyl, cyano, —NR′R″, —COR′, —NSO₂R′, —O(C2-C4 alkenyl), C2-C4alkenyl, —SO₂R′, —OCONR′R″ and —CR′═NOR″, or C1-C6 alkyl or C1-C6 alkoxygroups which are unsubstituted or substituted with one, two, three orfour, for example one, two, or three, for example one, unsubstitutedgroup selected from halogen, hydroxyl, amino, (C1-C4 alkyl)amino,di(C1-C4 alkyl)amino, C1-C4 alkoxy and —O—(C1-C4 alkyl)-O—(C1-C4 alkyl),preferably hydroxyl, C1-C4 alkoxy and —O—(C1-C4 alkyl)-O—(C1-C2 alkyl).Substituents on A1 when A1 is other than a bond can also includesubstituents of formula -(C1-C2 alkyl)-O—(C1-C4 alkyl)-NR′R″ where R′and R″ are the same or different and represent hydrogen or C1-C4 alkyl,or R′ and R″, together with the nitrogen atom to which they are bonded,form a piperazinyl or morpholinyl group which is unsubstituted orsubstituted with 1 or 2 C1-C4 alkyl groups. Preferred such substituentswhich are specific to the A1 group are those of formula —CH₂—O—(C2-C3alkyl)-NR′R″ where R′ and R″ are the same or different and representhydrogen or methyl, or R′ and R″, together with the nitrogen atom towhich they are bonded, form a piperazinyl or morpholinyl group which isunsubstituted or substituted with one methyl group. Unless otherwisespecified, aryl and heterocyclyl groups are not substituted with furtheraryl or heterocyclyl groups or with substituents containing further arylor heterocyclyl groups.

Examples of more preferred substituents on an aryl or heterocyclyl groupor moiety are unsubstituted substituents selected from halogen, —NR′R″,—CO₂R′, —CONR′R″, —OCONR′R″, —OCOR′, —COCF₃, hydroxyl and cyano, orC1-C6 alkyl or C1-C4 alkoxy which are unsubstituted or substituted witha hydroxyl, unsubstituted C1-C4 alkoxy or unsubstituted —O—(C1-C4alkyl)-O—(C1-C2 alkyl) group; wherein R′ and R″ are independentlyselected from hydrogen, unsubstituted C1-C4 alkyl and C1-C4 alkylsubstituted with a hydroxyl or unsubstituted C1-C4 alkoxy group.Typically none or one cyano substituent is present.

As used herein, a halogen is typically chlorine, fluorine, bromine oriodine, and is preferably chlorine, fluorine or bromine, more preferablychlorine or fluorine.

A1 preferably represents a bond, a phenyl, naphthyl, a 5- or 6-memberedheterocyclyl or 8- to 10-membered bicyclic heterocyclyl group, e.g. anunsaturated 8- to 10-membered bicyclic heterocyclyl group. Morepreferably A1 represents a bond or a phenyl, naphthyl, pyridyl,piperidinyl, benzofuranyl, indolyl, isoquinolinyl or quinolinyl group.Preferably A1 is other than a bond. A1 is typically other than apenicillin derivative, e.g. other than an oxo-thiaazabicyclo-heptane or-octane group. In a preferred embodiment A1 represents phenyl or a 5- or6-membered heterocyclyl group, more preferably A1 represents phenyl,pyridyl or piperidinyl. Most preferably A1 represents phenyl.

A1 may be unsubstituted or substituted with one, two or threesubstituents selected from the unsubstituted groups halogen, —CO₂R′,—CONR′R″, —OCOR′, hydroxyl, cyano, —NR′R″, —COR′, NSO₂R′, —O(C2-C4alkenyl), —C2-C4 alkenyl, —SO₂R′, —OCONR′R″ and —CR′═NOR″, and fromC1-C6 alkyl and C1-C4 alkoxy which are unsubstituted or substituted witha further unsubstituted C1-C4 alkoxy group; wherein R′ and R″ areindependently hydrogen or C1-C4 alkyl. A1 may also be substituted with agroup of formula -(C1-C2 alkyl)-O—(C1-C4 alkyl)-NR′R″ where R′ and R″are the same or different and represent hydrogen or C1-C4 alkyl, or R′and R″, together with the nitrogen atom to which they are bonded, form apiperazinyl or morpholinyl group which is unsubstituted or substitutedwith 1 or 2 C1-C4 alkyl groups. When a substituent of formula -(C1-C2alkyl)-O—(C1-C4 alkyl)-NR′R″ is present, preferably there are no othersubstituents on the A1 group. Typically only one cyano group is present.Preferred substituents are unsubstituted C1-C4 alkyl, C1-C4 alkylsubstituted with an unsubstituted C1-C4 alkoxy group, unsubstitutedC1-C4 alkoxy, —CO₂H and halogen, and a group of formula -(C1-C2alkyl)-O—(C1-C4 alkyl)-NR′R″. More preferred substituents areunsubstituted C1-C4 alkyl, C1-C4 alkyl substituted with an unsubstitutedC1-C4 alkoxy group, unsubstituted C1-C4 alkoxy, —CO₂H and halogen. Inone embodiment, A1 is unsubstituted.

n is one or two, preferably one. When n is 2, preferably A1 is phenyl,each L1 is the same or different and represents piperazinyl ormethylene, and each R1 is the same or different and represents pyridinylor morpholinyl.

L1 preferably represents a bond, a 5- to 7-membered heterocyclyl groupor a C1-C6 alkylene group wherein none, one or two —CH₂— groups areindependently replaced by —O— or —NR′—, wherein R′ is hydrogen,unsubstituted C1-C4 alkyl or C1-C4 alkyl substituted with anunsubstituted C1-C4 alkoxy group.

When L1 represents a 5- to 7-membered heterocyclyl group, it may belinked to A1 and R1 via a carbon atom or a heteroatom. Preferred 5- to7-membered heterocyclyl groups are saturated groups which contains atleast one nitrogen atom, for example one or two nitrogen atoms, whereinthe heterocyclyl group is linked to at least one of A1 and R1,preferably both of A1 and R1, via a nitrogen atom. Examples of suitableheterocycles for L1 include piperazinyl, pyrrolidinyl, oxazolyl,morpholinyl, piperidinyl and 1,4-diazepanyl. Preferred examples ofsuitable heterocycles for L1 include piperazinyl and 1,4-diazepanyl,especially piperazinyl. When L1 represents a 5- to 7-memberedheterocyclyl group, it is typically unsubstituted or substituted with anunsubstituted group selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy andhalogen. Hydroxy substituents are preferred. Preferably, when L1represents a 5- to 7-membered heterocyclyl group, it is unsubstituted.

L1 is most preferably a saturated 5- to 7-membered heterocyclyl groupcontaining one or two nitrogen atoms, or an unsubstituted C1-C6 alkylenegroup wherein none, one or two —CH₂— groups are independently replacedwith —O— or —NR′—, wherein R′ is hydrogen, unsubstituted C1-C4 alkyl orC1-C4 alkyl substituted with an unsubstituted C1-C4 alkoxy group. In oneembodiment, L1 is a saturated 5- to 7-membered heterocyclyl group,preferably a piperazinyl or 1,4-diazepanyl group.

When L1 is an unsubstituted C1-C6 alkylene group wherein none, one ortwo —CH₂— groups are independently replaced with —O— or —NR′—, suitablegroups include C4 or C5 alkylene groups where two —CH₂— moieties(preferably one or both terminal —CH₂-moieties) are replaced by —O— or—NR′— where R′ is hydrogen or unsubstituted C1-C2 alkyl. For example,preferred L1 groups in this category include —NMe-CH₂—CH₂—NMe-,—NH—CH₂—CH₂—O—, —O—CH₂—CH₂—NMe-, —O—CH₂—CH₂—O—, —NMe-CH₂—CH₂—NH—,—NH—CH₂—CH₂—NH—, —NH—CH₂—CH₂—NMe-, —CH₂—CH₂—CH₂—NMe- and—NMe-CH₂—CH₂—CH₂—NMe-. Most preferably L1 is piperazinyl.

R1 preferably represents hydrogen, unsubstituted or substituted C1-C8alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —COR′ or —SO₂(C1-C4 alkyl), or agroup -A2, -L2-A2, -L3-A2, -A2-L3-A3 or -A4. More preferably R1represents hydrogen, an unsubstituted group selected from C1-C6 alkyl,C2-C6 alkenyl, C2-C6 alkynyl, —CO(C1-C4 alkyl) and —SO₂(C1-C4 alkyl), ora group -A2, -L2-A2, -L3-A2, -A2-L3-A3 or -A4. When L1 is a bond, R1preferably represents hydrogen or a group -A2, L2-A2, A2-L3-A3 or A4.When L1 is other than a bond, R1 is preferably hydrogen, a C1-C6 alkylgroup, a C2-C6 alkenyl group, a C2-C6 alkynyl group, unsubstituted—CO—(C1-C4-alkyl), unsubstituted —SO₂(C1-C4 alkyl) or a group -A2,L2-A2, -L3-A2 or -A2-L3-A3. In one embodiment, R1 is preferably a group-A2, -L2-A2, -L3-A2 or -A2-L3-A3, more preferably a group -A2.

In a preferred embodiment R1 represents unsubstituted or substitutedC1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —COR′ or —SO₂(C1-C4 alkyl),or a group -A2, -L2-A2, -L3-A2, -A2-L3-A3 or -A4. More preferably R1represents an unsubstituted group selected from C1-C6 alkyl, C2-C6alkenyl, C2-C6 alkynyl and —SO₂(C1-C4 alkyl), or a group -A2, -L2-A2,-L3-A2, -A2-L3-A3 or -A4. When L1 is a bond, R1 preferably representsA2, L2-A2, A2-L3-A3 or A4. When L1 is other than a bond, R1 ispreferably a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynylgroup, unsubstituted —SO₂(C1-C4 alkyl) or a group -A2, L2-A2, -L3-A2 or-A2-L3-A3.

When R1 represents an alkyl, alkenyl or alkynyl group it is preferablyC1-C6 alkyl, C2-C6 alkenyl or C3-C6 alkynyl, more preferably C1-C6 alkyl(e.g. C3 or C4 alkyl), C3-C6 alkenyl or C3-C6 alkynyl. The alkyl,alkenyl and alkynyl groups are unsubstituted or substituted with 1, 2 or3 substituents selected from halogen (e.g. fluorine), hydroxyl, amino,C1-C4 alkoxy, CO₂H and CO₂(C1-C4 alkyl). Halogen, e.g. fluorine, ispreferred. The substituents are themselves unsubstituted. Preferably,when R1 represents an alkyl, alkenyl or alkynyl group it isunsubstituted.

A2 preferably represents C3-C6 cycloalkyl, phenyl or a 5- to 12-memberedheterocyclyl group. Preferably A2 represents phenyl or a 5- or6-membered heterocyclyl group. Preferred heterocyclyl groups includemonocyclic, saturated or unsaturated, 5- to 6-membered rings, each ofwhich may contain one, two or three, e.g. one or two, heteroatomsselected from N, O and S. Unsaturated 5- or 6-membered rings includeoxazolyl, isoxazolyl, imidazolyl, furanyl, thiophenyl, pyrimidinyl andpyridinyl, preferably pyridinyl. Saturated rings are preferably6-membered rings, for example piperidinyl, morpholinyl andtetrahydropyranyl, e.g. morpholinyl or tetrahydropyranyl. In oneembodiment, A2 represents phenyl or pyridinyl, especially pyridinyl.

A2 may be unsubstituted or substituted by one, two or threesubstituents. Examples of suitable substituents are unsubstitutedsubstituents selected from halogen, —CO₂R′, —CONR′R″, OCOR′, hydroxyl,cyano, —NR′R″, —COR′, —NSO₂R′, —O(C2-C4 alkenyl), C2-C4 alkenyl, —SO₂R′,—OCONR′R″ and —CR′═NOR″, or C1-C6 alkyl or C1-C6 alkoxy groups which areunsubstituted or substituted with one, two, three or four, for exampleone, two, or three, for example one, unsubstituted group selected fromhalogen, hydroxyl, amino, (C1-C4 alkyl)amino, di(C1-C4 alkyl)amino,C1-C4 alkoxy and —O—(C1-C4 alkyl)-O—(C1-C4 alkyl), preferably hydroxyl,C1-C4 alkoxy and —O—(C1-C4 alkyl)-O—(C1-C2 alkyl).

Preferred substituents on A2 are unsubstituted substituents selectedfrom halogen, —NR′R″, —CO₂R′, —CONR′R″, —OCONR′R″, —OCOR′, —COCF₃,hydroxyl and cyano, or C1-C6 alkyl or C1-C4 alkoxy which areunsubstituted or substituted with a hydroxyl, unsubstituted C1-C4 alkoxyor unsubstituted —O—(C1-C4 alkyl)-O—(C1-C2 alkyl) group; wherein R′ andR″ are independently selected from hydrogen, unsubstituted C1-C4 alkyland C1-C4 alkyl substituted with a hydroxyl or unsubstituted C1-C4alkoxy group. Typically none or one cyano substituent is present.

Particularly preferred substituents on A2 are halogen, —COCF₃, —OCONR′R″and —NR′R″, and C1-C4 alkyl and C1-C4 alkoxy groups which areunsubstituted or substituted with —OH, —OMe, —OEt or —O(C1-C4alkyl)-O(C1-C2 alkyl), wherein R′ and R″ are independently selected fromhydrogen, unsubstituted C1-C4 alkyl and C1-C4 alkyl substituted with ahydroxyl or unsubstituted C1-C4 alkoxy group. Most preferredsubstituents are C1-C2 alkyl and C1-C2 alkoxy, especially methyl.

In one embodiment, L2 represents —SO₂—.

In one embodiment, L3 represents a bond or a C1-C4 alkylene group inwhich none, one or two —CH₂— moieties are independently replaced with—O— or —NR′— wherein R′ represents hydrogen or unsubstituted C1-C4alkyl. In another embodiment, L3 represents a bond or an unsubstitutedC1-C4 alkylene group. Preferably, L3 represents a bond or unsubstitutedmethylene, ethylene or propylene, e.g. unsubstituted methylene orethylene, more preferably unsubstituted methylene. In the group -L3-A2,L3 preferably represents unsubstituted methylene, ethylene or propylene,e.g. unsubstituted methylene or ethylene, more preferably unsubstitutedmethylene.

In one embodiment, A3 represents phenyl or a 5- to 12-memberedheterocyclyl group. Preferred heterocyclyl groups include monocyclic,unsaturated or saturated 5- to 6-membered rings, each of which maycontain one, two or three, e.g. one or two, heteroatoms selected from N,O and S. Saturated 5- or 6-membered rings are preferred, e.g.morpholinyl, tetrahydropyranyl, piperidinyl or piperazinyl, inparticular morpholinyl and piperazinyl.

A3 may be unsubstituted or substituted by one, two or threeunsubstituted groups selected from C1-C4 alkyl, C1-C4 alkoxy, halogen,—CO₂R′, —CONR′R″, —OCOR′, hydroxyl, cyano, —NR′R″, —COR′, —NSO₂R′,—O(C2-C4 alkenyl), —C2-C4 alkenyl, —SO₂R′, —OCONR′R″ and —CR′═NOR″,wherein R′ and R″ are independently hydrogen or C1-C4 alkyl. Typicallyonly one cyano group is present. Preferred substituents are C1-C4 alkyl,C1-C4 alkoxy and halogen.

A4 is preferably an unsubstituted or substituted 5- to 6-memberedheterocyclyl group wherein 1 ring carbon atom has been replaced with agroup selected from >C(═O), >S(═O)₂, >C(═NOR7) where R7 is hydrogen or aC1-C4 alkyl group, >C═CH₂ or >C(—OCH₂CH₂O—). Preferably A4 is anunsubstituted or substituted 5- to 6-membered heterocyclyl group wherein1 ring carbon atom has been replaced with >C═CH₂. Preferred A4 groupsinclude unsubstituted or substituted dioxothiomorpholinyl,methoxyiminopiperidinyl, methoxyiminopyrrolidinyl, methylenepiperidinyl,dioxoazaspirodecyl and oxadihydropyrazolyl groups. The A9 groups can beunsubstituted or substituted; more preferably they are unsubstituted.Unsubstituted methylenepiperidinyl is preferred.

In one embodiment, R6 is hydrogen or methyl, more preferably R6 ishydrogen.

In one embodiment, R5 is hydrogen, phenyl, a monocyclic 5- to 8-memberedheterocyclyl ring, a C3-C6 cycloalkyl group, an unsubstituted C1-C8alkyl or a C1-C8 alkyl substituted with a C1-C4 alkoxy group. When R5 isC1-C8 alkyl substituted with C1-C4 alkoxy, preferably it is -(C1-C2alkyl)-O(C1-C2 alkoxy), more preferably —CH₂—CH₂—OMe. More preferably R5is hydrogen, phenyl, a monocyclic 5- to 8-membered heterocyclyl ring, aC3-C6 cycloalkyl group or unsubstituted C1-C8 alkyl. The heterocyclylring is typically pyridinyl, thiophenyl, furanyl, tetrahydropyranyl orpiperidinyl. The cycloalkyl group is typically cyclobutyl, which isitself preferably unsubstituted. The phenyl and heterocyclyl groups areunsubstituted or substituted with one, two or three unsubstitutedsubstituents selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, —CO₂R′,—CONR′R″, —OCOR′ or cyano, wherein R′ and R″ are independently selectedfrom hydrogen and C1-C4 alkyl. Typically only one cyano substituent ispresent. Most preferably R5 is hydrogen or an unsubstituted phenyl.

In another embodiment, R5 is hydrogen, unsubstituted or substitutedphenyl, unsubstituted C3-C6 cycloalkyl, unsubstituted or substitutedpyridinyl or piperidinyl, or unsubstituted thiophenyl, furanyl ortetrahydropyranyl, the substituents being selected from halogen,unsubstituted C1-C4 alkyl, unsubstituted C1-C4 alkoxy or cyano, e.g.halogen, unsubstituted C1-C4 alkyl or unsubstituted C1-C4 alkoxy. Inthis embodiment R5 is, for example, hydrogen, unsubstituted orsubstituted phenyl or unsubstituted pyridinyl, thiophenyl or furanyl.

Preferably in this embodiment, R5 is hydrogen, unsubstituted orsubstituted phenyl, unsubstituted C3-C6 cycloalkyl, unsubstituted orsubstituted pyridinyl or piperidinyl, or unsubstituted thiophenyl,furanyl or tetrahydropyranyl, the substituents being selected fromhalogen, unsubstituted C1-C4 alkyl, unsubstituted C1-C4 alkoxy or cyano,e.g. halogen, unsubstituted C1-C4 alkyl or unsubstituted C1-C4 alkoxy,or R5 is a C1-C8 alkyl group substituted with a C1-C4 alkoxy group. Inthis embodiment R5 is, for example, hydrogen, unsubstituted orsubstituted phenyl or unsubstituted pyridinyl, thiophenyl or furanyl, oris a group —CH₂—CH₂—OMe.

In another embodiment, R5 is a group —B1-B2 or —B3. When R2 is —B1-B2,B1 is typically an unsubstituted or substituted phenyl group. Morepreferably B1 is an unsubstituted phenyl group. When R5 is —B1-B2, B2 istypically an unsubstituted or substituted phenyl or 5- to 6-memberedheterocyclyl group, more preferably an unsubstituted or substitutedphenyl, piperazinyl or morpholinyl group, e.g. an unsubstituted orsubstituted phenyl or piperazinyl group. When substituted, preferredsubstituents are 1 or 2 groups selected from halogen atoms and C1-C4alkyl and C1-C4 alkoxy groups, more preferably halogen atoms or C1-C2alkyl or C1-C2 alkoxy groups, more preferably C1-C2 alkyl groups such asmethyl.

When R5 is B3, typically B3 is a 5- to 6-membered heterocyclyl groupwhere 1 or 2 ring carbon atoms are replaced with >C(═O)—,>S(═O)₂—, >C(═NOR11), >C(NR11), >C(═CH₂) or >C(—OCH₂CH₂O—), where R11 ishydrogen or C1-C4 alkyl. Preferably R11 is hydrogen or C1-C2 alkyl, morepreferably hydrogen or methyl. When R5 is B3, more preferably B3 is a 5-to 6-membered heterocyclyl group where 1 ring carbon atom is replacedwith >C(═O)—, >S(═O)₂—, >C(═NOR11), >C(NR11), >C(═CH₂) or>C(—OCH₂CH₂O—), where R11 is hydrogen or C1-C2 alkyl, more preferably 1ring carbon atom is replaced with >C(═O). A preferred B3 group isoxo-dihydropyridinyl. When R5 is B3, B3 can be unsubstituted orsubstituted. Preferably it is unsubstituted.

In one embodiment, R2 and R3 independently represent C6-C10 aryl, a 5-to 12-membered heterocyclyl group, C3-C6 cycloalkyl, hydrogen, halogen,C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, —OR′, —SR′,—SOR′, —SO₂R′, —SO₂NR′R″, —SO₃H, —NR′R″, —NR′COR′, —CO₂R′, —CONR′R″,—COR′, —OCOR′, —CF₃, —NSO₂R′ or —OCONR′R″, or a group (C1-4) alkyl-A5,wherein none, one or two —CH₂— groups are independently replaced by —O—,—S— or —NR′— and wherein A5 represents C6-10 aryl or a 5- to 12-memberedheterocyclyl group;

When R2 and R3 represent or contain C6-C10 aryl or a 5- to 12-memberedheterocyclyl group, the aryl or heterocyclyl group is typically phenylor a 5- or 6-membered, saturated or unsaturated heterocyclyl group.Typically none or one of R2 and R3 represents or contains an aryl orheterocyclyl group. Examples of suitable heterocyclyl groups includesaturated rings such as pyrrolidinyl, morpholinyl, piperazinyl,tetrahydropyranyl and piperidinyl, and unsaturated rings such asoxazolyl, furanyl, thiophenyl, pyridinyl and pyrimidinyl, e.g. furanyl,thiphenyl, pyridinyl and pyrimidinyl. Bicyclic 8- to 10-membered ringsmay also be present at R2 and R3, for example indolyl, benzofuranyl andbenzothiophenyl rings.

An aryl or heterocyclyl group or moiety on R2 or R3 may be unsubstitutedor substituted on any ring atom. Typically it is unsubstituted orsubstituted with one, two or three substituents. Examples of suitablesubstituents are unsubstituted substituents selected from halogen,—CO₂R′, —CONR′R″, OCOR′, hydroxyl, cyano, —NR′R″, —COR′, —NSO₂R′,—O(C2-C4 alkenyl), C2-C4 alkenyl, —SO₂R′, —OCONR′R″ and —CR′═NOR″, orC1-C6 alkyl or C1-C6 alkoxy groups which are unsubstituted orsubstituted with one, two, three or four, for example one, two, orthree, for example one, unsubstituted group selected from halogen,hydroxyl, amino, (C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, C1-C4 alkoxyand —O—(C1-C4 alkyl)-O—(C1-C4 alkyl), preferably hydroxyl, C1-C4 alkoxyand —O—(C1-C4 alkyl)-O—(C1-C2 alkyl).

Preferred substituents are unsubstituted substituents selected fromhalogen, —NR′R″, —CO₂R′, —CONR′R″, —OCONR′R″, —OCOR′, —COCF₃ andhydroxyl, or C1-C6 alkyl or C1-C4 alkoxy which are unsubstituted orsubstituted with a hydroxyl or unsubstituted C1-C4 alkoxy group; whereinR′ and R″ are independently selected from hydrogen, unsubstituted C1-C4alkyl and C1-C4 alkyl substituted with a hydroxyl or unsubstituted C1-C4alkoxy group. More preferred substituents are halogen, unsubstitutedC1-C4 alkyl (e.g. methyl) and unsubstituted C1-C4 alkoxy groups, inparticular methyl.

In this embodiment, R2 preferably represents phenyl, hydrogen,—COO(C1-C4 alkyl), halogen, unsubstituted C3-C6 cycloalkyl, or a C1-C4alkyl, C2-C4 alkenyl or C1-C4 alkoxy group which is unsubstituted orsubstituted with —SMe, —SEt, hydroxyl, di(C1-C4 alkyl)amino, —COO(C1-C4alkyl), —CONR′R″, —NR′CO(C1-C4 alkyl), unsubstituted C1-C4 alkoxy orC1-C4 alkoxy substituted with —OMe or —OEt, where R′ and R″ are the sameor different and represent hydrogen or unsubstituted C1-C4 alkyl; or R2represents a group (C1-C4) alkyl-A5, wherein none or one —CH₂— groupsare independently replaced by —O—, —S— or —NR′— and wherein A5represents phenyl, pyridinyl or oxazolyl.

More preferably, R2 represents unsubstituted phenyl, hydrogen, halogen,unsubstituted C1-C4 alkoxy, unsubstituted C2-C4 alkenyl, unsubstitutedC1-C4 alkyl, or C1-C4 alkyl or C2-C4 alkenyl substituted with —OMe,—OEt, —OPr, —OBu, —OCH₂CH₂OMe, —SMe, hydroxy, di(C1-C4 alkyl)amino,—COO(C1-C4 alkyl), —CONR′R″ or —NR′CO(C1-C4 alkyl) where R′ and R″ arethe same or different and represent hydrogen or unsubstituted C1-C4alkyl; or R2 represents a group (C1-C4) alkyl-A5, wherein none or one—CH₂— groups are independently replaced by —O— and wherein A5 representsphenyl, pyridinyl or oxazolyl, each of which is unsubstituted orsubstituted with one or two substituents selected from halogen, C1-C4alkyl and C1-C4 alkoxy.

In this embodiment, more preferably R2 represents phenyl, hydrogen,halogen, unsubstituted C2-C4 alkenyl, unsubstituted C3-C6 cycloalkyl, ora C1-C4 alkyl or C1-C4 alkoxy group which is unsubstituted orsubstituted with —OMe or —OEt. More preferably, R2 representsunsubstituted phenyl, hydrogen, halogen, unsubstituted C1-C4 alkoxy,unsubstituted C1-C4 alkyl, or C1-C4 alkyl substituted with —OMe or —OEt.Most preferably, R2 represents unsubstituted C1-C4 alkyl, e.g. methyl.

In this embodiment, R3 preferably represents hydrogen, halogen,unsubstituted phenyl, unsubstituted C2-C4 alkenyl, or a C1-C4 alkyl orC1-C4 alkoxy group which is unsubstituted or substituted with —OMe or—OEt. More preferably, R3 represents hydrogen, halogen, unsubstitutedphenyl, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 alkyl, or C1-C4alkyl substituted with —OMe or —OEt. In this embodiment, still morepreferably R3 represents hydrogen, halogen, unsubstituted C2-C4 alkenyl,or a C1-C4 alkyl or C1-C4 alkoxy group which is unsubstituted orsubstituted with —OMe or —OEt. More preferably, R3 represents hydrogen,halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 alkyl, or C1-C4alkyl substituted with —OMe or —OEt. Most preferably R3 representshydrogen or unsubstituted C1-C4 alkyl, e.g. methyl.

In an alternative embodiment, R2 and R3 together with the ring atoms towhich they are bonded form a 5- to 7-membered, at least partiallysaturated ring containing a nitrogen atom from the adjacent pyrrolering, and optionally one or two further heteroatoms selected from N, Oand S, with the proviso that R2 and R3 do not form, together with thepyrrole ring to which they are bonded, an indolizine ortetrahydroindolizine ring. Preferred heterocyclyl rings are at leastpartially saturated 5- or 6-membered rings containing a nitrogen atomfrom the adjacent pyrrole ring and none or one further heteroatomselected from N and O. Examples of preferred rings are piperazinyl,morpholinyl and pyrrolidinyl. Alternative preferred heterocyclyl ringsinclude saturated 5- to 7-membered rings containing a nitrogen atom fromthe adjacent pyrrole ring and none or one further heteroatom selectedfrom N and O, for example azepanyl.

The heterocyclyl ring formed by R2 and R3 may be unsubstituted orsubstituted on any ring atom. Typically, none, one or two substituentsare present. Examples of suitable substituents on the R2/R3 ring areunsubstituted substituents selected from halogen, —CO₂R′, —CONR′R″,OCOR′, hydroxyl, cyano, —NR′R″, —COR′, —NSO₂R′, —O(C2-C4 alkenyl), C2-C4alkenyl, —SO₂R′, —OCONR′R″ and —CR′═NOR″, or C1-C6 alkyl or C1-C6 alkoxygroups which are unsubstituted or substituted with one, two, three orfour, for example one, two, or three, for example one, unsubstitutedgroup selected from halogen, hydroxyl, amino, (C1-C4 alkyl)amino,di(C1-C4 alkyl)amino, C1-C4 alkoxy and —O—(C1-C4 alkyl)-O—(C1-C4 alkyl),preferably hydroxyl, C1-C4 alkoxy and —O—(C1-C4 alkyl)-O—(C1-C2 alkyl).

Preferred substituents are unsubstituted substituents selected fromhalogen, —NR′R″, —CO₂R′, —CONR′R″, —OCONR′R″, —OCOR′, —COCF₃ andhydroxyl, or C1-C6 alkyl or C1-C4 alkoxy which are unsubstituted orsubstituted with a hydroxyl or unsubstituted C1-C4 alkoxy group; whereinR′ and R″ are independently selected from hydrogen, unsubstituted C1-C4alkyl and C1-C4 alkyl substituted with a hydroxyl or unsubstituted C1-C4alkoxy group. More preferred substituents are halogen, unsubstitutedC1-C4 alkyl (e.g. methyl) and unsubstituted C1-C4 alkoxy groups, inparticular methyl.

Typically, when R4 is or contains an aryl or heterocyclyl group, thearyl or heterocyclyl group is phenyl, benzyl or pyridyl. The aryl orheterocyclyl group may be unsubstituted or substituted on any ring atom,for example with one, two or three substituents. Preferred substituentsare unsubstituted substituents selected from halogen, —NR′R″, —CO₂R′,—CONR′R″, —OCONR′R″, —OCOR′, —COCF₃ and hydroxyl, or C1-C6 alkyl orC1-C4 alkoxy which are unsubstituted or substituted with a hydroxyl orunsubstituted C1-C4 alkoxy group; wherein R′ and R″ are independentlyselected from hydrogen, unsubstituted C1-C4 alkyl and C1-C4 alkylsubstituted with a hydroxyl or unsubstituted C1-C4 alkoxy group. Morepreferred substituents are halogen, unsubstituted C1-C4 alkyl (e.g.methyl) and unsubstituted C1-C4 alkoxy groups, in particular methyl ormethoxy. More preferably, the aryl or heterocyclyl ring isunsubstituted.

In one embodiment, R4 represents hydrogen, halogen, phenyl, C1-C4 alkyl,C2-C4 alkenyl, C2-C4 alkynyl, —OR′, —CO₂R′, CONR′R″, —COR′, —CN, —NO₂,—NR′R″ or —CF₃ wherein R′ and R″ are independently hydrogen or C1-C4alkyl, more preferably R4 represents hydrogen, halogen, phenyl, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, —OR′, —CO₂R′, CONR′R″, —COR′, —CN,—NO₂, —NR′R″ or —CF₃ wherein R′ and R″ are independently hydrogen orC1-C4 alkyl. In another embodiment R4 represents hydrogen, halogen orC1-C4 alkyl, preferably hydrogen. Where R4 is capable of beingsubstituted, it is typically unsubstituted or substituted with onehalogen atom, more preferably it is unsubstituted.

In one embodiment, when R5 is phenyl or thienyl then preferably R4 ishydrogen. In another embodiment when R4 is phenyl preferably R5 ishydrogen.

Typically, Z is halogen, OR′, SR′, —NR′R′, —CO₂R′, —CONR′R″, —COR′,—OCOR′ or CN, wherein R′ and R″ are independently hydrogen or C1-C4alkyl.

In a preferred embodiment of the invention, R1 represents hydrogen,unsubstituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —COR′ or—SO₂(C1-C4 alkyl), or a group -A2, -L2-A2, -L3-A2, -A2-L3-A3 or -A4;

A1 represents a bond, phenyl, naphthyl, a 5- or 6-membered monocyclicheterocyclyl group, or an 8- to 10-membered bicyclic heterocyclyl group;

A2 and A3 are the same or different and represent phenyl or a 5- to12-membered heterocyclyl group;

A4 represents a 5- to 6-membered heterocyclyl group wherein 1 ringcarbon atom has been replaced with a group selected from >C(═O),>S(═O)₂, >C(═NOR7) where R7 is hydrogen or a C1-C4 alkyl group, >C═CH₂or >C(—OCH₂CH₂O—);

L1 represents a bond, a 5- to 7-membered heterocyclyl group which isunsubstituted or substituted with an unsubstituted group selected fromC1-C4 alkyl, C1-C4 alkoxy, hydroxy and halogen, or a C1-C6 alkylenegroup wherein none, one or two —CH₂— groups are independently replacedby —O— or —NR′—, wherein R′ is hydrogen, unsubstituted C1-C4 alkyl orC1-C4 alkyl substituted with an unsubstituted C1-C4 alkoxy group;

L2 is as defined above;

L3 represents a bond or a C1-C4 alkylene group in which none, one or two—CH₂— moieties are independently replaced with —O— or —NR′—, wherein R′represents hydrogen or unsubstituted C1-C4 alkyl;

n is as defined above;

R6 represents hydrogen or unsubstituted C1-C4 alkyl;

R5 represents hydrogen, phenyl, a monocyclic 5- to 8-memberedheterocyclyl ring, an unsubstituted C3-C6 cycloalkyl group, anunsubstituted C1-C8 alkyl or a C1-C8 alkyl substituted with a C1-C4alkoxy;

either (i) R2 represents phenyl, hydrogen, —COO(C1-C4 alkyl), halogen,unsubstituted C3-C6 cycloalkyl, or a C1-C4 alkyl, C2-C4 alkenyl or C1-C4alkoxy group which is unsubstituted or substituted with —SMe, —SEt,hydroxyl, di(C1-C4 alkyl)amino, —COO(C1-C4 alkyl), —CONR′R″,—NR′CO(C1-C4 alkyl), unsubstituted C1-C4 alkoxy or C1-C4 alkoxysubstituted with —OMe or —OEt, where R′ and R″ are the same or differentand represent hydrogen or unsubstituted C1-C4 alkyl; or R2 represents agroup (C1-C4) alkyl-A5, wherein none or one —CH₂— groups areindependently replaced by —O—, —S— or —NR′— and wherein A5 representsphenyl, pyridinyl or oxazolyl; and R3 represents hydrogen, halogen,unsubstituted C2-C4 alkenyl, or a C1-C4 alkyl or C1-C4 alkoxy groupwhich is unsubstituted or substituted with —OMe or —OEt; or (ii) R2 andR3 together with the ring atoms to which they are bonded form an atleast partially saturated 5- or 6-membered ring containing a nitrogenatom from the adjacent pyrrole ring and none or one further heteroatomselected from N and O, with the proviso that R2 and R3 do not form,together with the pyrrole ring to which they are bonded, an indolizineor tetrahydroindolizine ring; and

R4 represents hydrogen, halogen, phenyl, or an unsubstituted groupselected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, —OR′, —CO₂R′,CONR′R″, —COR′, —CN, —NO₂, —NR′R″ or —CF₃, wherein R′ and R″ areindependently hydrogen or C1-C4 alkyl;

wherein the aryl and heterocyclyl rings formed by A1, A2, A3, A4, R5, R2or R2 and R3 are unsubstituted or substituted with one, two or threesubstituents selected from the unsubstituted groups halogen, —CO₂R′,—CONR′R″, OCOR′, hydroxyl, cyano, —NR′R″, —COR′, —NSO₂R′, —O(C2-C4alkenyl), C2-C4 alkenyl, —SO₂R′, —OCONR′R″ and —CR′═NOR″, and from C1-C6alkyl and C1-C6 alkoxy groups which are unsubstituted or substitutedwith one, two, three or four unsubstituted groups selected fromhydroxyl, C1-C4 alkoxy and —O—(C1-C4 alkyl)-O—(C1-C2 alkyl), and whereinthe group A1 can additionally or alternatively be substituted by a groupof formula —(C1-C2 alkyl)-O—(C1-C4 alkyl)-NR′R″ where R′ and R″ are thesame or different and represent hydrogen or C1-C4 alkyl, or R′ and R″,together with the nitrogen atom to which they are bonded, form apiperazinyl or morpholinyl group which is unsubstituted or substitutedwith 1 or 2 C1-C4 alkyl groups.

In this preferred embodiment more preferably R1 represents unsubstitutedC1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —COR′ or —SO₂(C1-C4 alkyl),or a group -A2, -L2-A2, -L3-A2, -A2-L3-A3 or -A4. Preferably A1represents phenyl or a 5- or 6-membered heterocyclyl group. PreferablyR5 represents hydrogen, phenyl, a monocyclic 5- to 8-memberedheterocyclyl ring, an unsubstituted C3-C6 cycloalkyl group orunsubstituted C1-C8 alkyl. Preferably R4 represents hydrogen, halogen,or an unsubstituted group selected from C1-C4 alkyl, C2-C4 alkenyl,C2-C4 alkynyl, —OR′, —CO₂R′, CONR′R″, —COR′, —CN, —NO₂, —NR′R″ or —CF₃,wherein R′ and R″ are independently hydrogen or C1-C4 alkyl. In thispreferred embodiment preferably the aryl and heterocyclyl rings formedby A1, A2, A3, A4, R5, R2 or R2 and R3 are unsubstituted or substitutedwith one, two or three substituents selected from the unsubstitutedgroups halogen, —CO₂R′, —CONR′R″, OCOR′, hydroxyl, cyano, —NR′R″, —COR′,—NSO₂R′, —O(C2-C4 alkenyl), C2-C4 alkenyl, —SO₂R′, —OCONR′R″ and—CR′═NOR″, and from C1-C6 alkyl and C1-C6 alkoxy groups which areunsubstituted or substituted with one, two, three or four unsubstitutedgroups selected from hydroxyl, C1-C4 alkoxy and —O—(C1-C4alkyl)-O—(C1-C2 alkyl).

Particularly preferred compounds for use in the invention are pyrrolederivatives of formula (Ia) and pharmaceutically or agriculturallyacceptable salts thereof:

wherein:

A1 represents a bond, phenyl, naphthyl, pyridyl, piperidinyl,benzofuranyl, indolyl, isoquinolinyl or quinolinyl, each of which may beunsubstituted or substituted with one or more substituents selected fromunsubstituted C1-C4 alkyl, C1-C4 alkyl substituted with an unsubstitutedC1-C4 alkoxy group, unsubstituted C1-C4 alkoxy, —CO₂H and halogen, orfrom a group of formula -(C1-C2 alkyl)-O—(C1-C4 alkyl)-NR′R″ where R′and R″ are the same or different and represent hydrogen or C1-C4 alkyl,or R′ and R″, together with the nitrogen atom to which they are bonded,form a piperazinyl or morpholinyl group which is unsubstituted orsubstituted with 1 or 2 C1-C4 alkyl groups;

n represents one or two, preferably one;

L1 represents a bond, a saturated 5- to 7-membered heterocyclyl groupcontaining one or two nitrogen atoms, or an unsubstituted C1-C6 alkylenegroup wherein none, one or two —CH₂— groups are independently replacedwith —O— or —NR′—, wherein R′ is hydrogen, unsubstituted C1-C4 alkyl orC1-C4 alkyl substituted with an unsubstituted C1-C4 alkoxy group, andwherein the heterocyclyl group is unsubstituted or substituted with anunsubstituted group selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy andhalogen;

when L1 is a bond, R1 represents hydrogen, -A2, —SO₂-A2, A2-L3-A3 or A4;and when L1 is other than a bond, R1 represents hydrogen or anunsubstituted group selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, —CO(C1-C4 alkyl) and —SO₂(C1-C4 alkyl), or a group -A2,—SO₂-A2, -L3-A2 or -A2-L3-A3;

A2 and A3 independently represent phenyl or a 5- or 6-memberedheterocyclyl group, wherein A2 and A3 are unsubstituted or substitutedwith one, two or three substituents selected from the unsubstitutedsubstituents halogen, —COCF₃, —OCONR′R″ and —NR′R″, and from C1-C4 alkyland C1-C4 alkoxy groups which are unsubstituted or substituted with —OH,—OMe, —OEt or —O(C1-C4 alkyl)-O(C1-C2 alkyl), wherein R′ and R″ areindependently selected from hydrogen, unsubstituted C1-C4 alkyl andC1-C4 alkyl substituted with a hydroxyl or unsubstituted C1-C4 alkoxygroup;

L3 represents a bond or unsubstituted methylene, ethylene or propylene;

A4 represents unsubstituted dioxothiomorpholinyl,methoxyiminopiperidinyl, methoxyiminopyrrolidinyl, methylenepiperidinyl,dioxoazaspirodecyl or oxadihydropyrazolyl;

R5 represents hydrogen, unsubstituted or substituted phenyl,unsubstituted C3-C6 cycloalkyl, unsubstituted or substituted pyridinylor piperidinyl, or unsubstituted thiophenyl, furanyl ortetrahydropyranyl, the substituents being selected from halogen,unsubstituted C1-C4 alkyl, unsubstituted C1-C4 alkoxy or R5 is a C1-C8alkyl group which is unsubstituted or substituted with a C1-C4 alkoxygroup; and

either (i) R2 represents unsubstituted phenyl, hydrogen, halogen,unsubstituted C1-C4 alkoxy, unsubstituted C2-C4 alkenyl, unsubstitutedC1-C4 alkyl, or C1-C4 alkyl or C2-C4 alkenyl substituted with —OMe,—OEt, —OPr, —OBu, —OCH₂CH₂OMe, —SMe, hydroxy, di(C1-C4 alkyl)amino,—COO(C1-C4 alkyl), —CONR′R″ or —NR′CO(C1-C4 alkyl) where R′ and R″ arethe same or different and represent hydrogen or unsubstituted C1-C4alkyl; or R2 represents a group (C1-C4) alkyl-A5, wherein none or one—CH₂— groups are independently replaced by —O— and wherein A5 representsphenyl, pyridinyl or oxazolyl, each of which is unsubstituted orsubstituted with one or two substituents selected from halogen, C1-C4alkyl and C1-C4 alkoxy; and R3 represents hydrogen, halogen,unsubstituted phenyl, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4alkyl, or C1-C4 alkyl substituted with —OMe or —OEt; or (ii) R2 and R3together with the ring atoms to which they are bonded form a substitutedor unsubstituted at least partially saturated 5- or 6-membered ringcontaining a nitrogen atom from the adjacent pyrrole ring and none orone further heteroatom selected from N and O, the substituents beingselected from unsubstituted C1-C4 alkyl and unsubstituted C1-C4 alkoxygroups.

In this more preferred embodiment, preferably A1 is other than a bond.More preferably A1 represents phenyl, pyridyl or piperidinyl, each ofwhich may be unsubstituted or substituted with one or more substituentsselected from unsubstituted C1-C4 alkyl, C1-C4 alkyl substituted with anunsubstituted C1-C4 alkoxy group, unsubstituted C1-C4 alkoxy, —CO₂H andhalogen. Preferably when L1 is a bond, R1 represents -A2, —SO₂-A2,A2-L3-A3 or A4; and when L1 is other than a bond, R1 represents anunsubstituted group selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl and —SO₂(C1-C4 alkyl), or a group -A2, —SO₂-A2, -L3-A2 or-A2-L3-A3. Preferably R5 represents hydrogen, unsubstituted orsubstituted phenyl, unsubstituted C3-C6 cycloalkyl, unsubstituted orsubstituted pyridinyl or piperidinyl, or unsubstituted thiophenyl,furanyl or tetrahydropyranyl, the substituents being selected fromhalogen, unsubstituted C1-C4 alkyl or unsubstituted C1-C4 alkoxy.Preferably either R2 represents unsubstituted phenyl, hydrogen, halogen,unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 alkyl, or C1-C4 alkylsubstituted with —OMe or —OEt, and R3 represents hydrogen, halogen,unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 alkyl, or C1-C4 alkylsubstituted with —OMe or —OEt; or R2 and R3 together with the ring atomsto which they are bonded form a substituted or unsubstituted at leastpartially saturated 5- or 6-membered ring containing a nitrogen atomfrom the adjacent pyrrole ring and none or one further heteroatomselected from N and O, the substituents being selected fromunsubstituted C1-C4 alkyl and unsubstituted C1-C4 alkoxy groups.

A further preferred embodiment provides pyrrole derivatives of formula(Ia) and pharmaceutically or agriculturally acceptable salts thereof,wherein:

A1 represents phenyl, which may be unsubstituted or substituted with oneor more substituents selected from unsubstituted C1-C4 alkyl, C1-C4alkyl substituted with an unsubstituted C1-C4 alkoxy group,unsubstituted C1-C4 alkoxy, —CO₂H and halogen, preferably A1 isunsubstituted or substituted with one group selected from F, Cl andmethyl, most preferably A1 is unsubstituted;

n represents one;

L1 represents an unsubstituted, saturated 5- to 7-membered heterocyclylgroup containing two nitrogen atoms, the heterocycle being attached toA1 and to R1 via a nitrogen atom, preferably L1 represents piperazinyl;

R1 represents unsubstituted C1-C6 alkyl, unsubstituted C2-C6 alkenyl, ora group -A2, —CH₂-A2 or -A2-CH₂-A3;

A2 and A3 independently represent phenyl or a 5- or 6-memberedheterocyclyl group, wherein A2 and A3 are unsubstituted or substitutedwith one, two or three substituents selected from the unsubstitutedsubstituents halogen, —COCF₃, —OCONR′R″ and —NR′R″, and from C1-C4 alkyland C1-C4 alkoxy groups which are unsubstituted or substituted with —OH,—OMe, —OEt or —O(C1-C4 alkyl)-O(C1-C2 alkyl), wherein R′ and R″ areindependently selected from hydrogen, unsubstituted C1-C4 alkyl andC1-C4 alkyl substituted with a hydroxyl or unsubstituted C1-C4 alkoxygroup;

R5 represents unsubstituted phenyl;

R2 represents hydrogen, or C1-C4 alkyl or C2-C4 alkenyl, each of whichmay be unsubstituted or substituted with —OMe, —OEt, —OPr, —OBu,—OCH₂CH₂OMe, —SMe, hydroxy, di(C1-C4 alkyl)amino, —COO(C1-C4 alkyl),—CONR′R″ or —NR′CO(C1-C4 alkyl) where W and R″ are the same or differentand represent hydrogen or unsubstituted C1-C4 alkyl; or R2 represents agroup (C1-C4) alkyl-A5, wherein none or one —CH₂— groups areindependently replaced by —O— and wherein A5 represents phenyl,pyridinyl or oxazolyl, each of which is unsubstituted or substitutedwith one or two substituents selected from halogen, C1-C4 alkyl andC1-C4 alkoxy; and

R3 represents hydrogen or C1-C4 alkyl which is unsubstituted orsubstituted with —OMe or —OEt.

In a preferred aspect of this embodiment, A1 is a phenyl group which isunsubstituted or substituted with F, Cl or methyl, preferably A1 isunsubstituted phenyl; L1 is piperazinyl and is linked to A1 and R1 via anitrogen atom; and R1 is unsubstituted C1-C6 alkyl, unsubstituted C2-C6alkenyl, or piperidinyl, wherein the piperidinyl group is unsubstitutedor substituted with one, two or three substituents selected fromunsubstituted C1-C4 alkyl groups. More preferably, R1 is piperidinylwhich is substituted with two methyl groups.

In a further preferred aspect of this embodiment, R2 and R3 areindependently selected from hydrogen and unsubstituted C1-C4 alkylgroups, preferably methyl.

A particular embodiment of the invention relates to pyrrole derivativesof formula (I) and pharmaceutically acceptable salts thereof, for use ina method of treatment of a human or animal body by therapy. In thisembodiment, R6 is hydrogen and A1 is a bond, a C3-C6 cycloalkyl or anunsubstituted or substituted C6-C10 aryl, 5- or 6-membered heterocyclylor 8- to 10-membered bicyclic heterocyclyl group. Preferably, A1represents a C3-C6 cycloalkyl or an unsubstituted or substituted C6-C10aryl, 5- or 6-membered heterocyclyl or unsaturated 8- to 10-memberedbicyclic heterocyclyl group. More preferably, A1 represents a phenyl,naphthyl, pyridyl, piperidinyl, benzofuranyl, indolyl, isoquinolinyl orquinolinyl group. Possible substituents on A1 are as defined above.

In this embodiment, when A1 is a bond, (i) -L1-R1 is not hydrogen, (ii)when R2 is unsubstituted or substituted phenyl and R3 to R5 are allhydrogen, -L1-R1 is not unsubstituted or substituted benzyl orsubstituted phenethyl, and (iii) when R6 is hydrogen and R3 to R5 areall hydrogen or chlorine, then none of L1, L3 and L1-R1 represents anunsubstituted or substituted C1-C4 alkyl group. Preferably, when A1 is abond, -L1-R1 is other than hydrogen, unsubstituted or substitutedbenzyl, substituted phenethyl or unsubstituted or substituted C2-C4alkyl. More preferably, A1 is not a bond.

In this embodiment, R4 represents hydrogen, halogen, C1-C8 alkyl, C2-C8alkenyl, C2-C8 alkynyl, —OR′, —CONR′R″, —COR′, —CN, —NO₂, —NR′R″, CF₃,—Y—Z, C6-C10 aryl, or 5- to 12-membered heterocyclyl group, or a groupof formula -Alk⁶-L5-A12, where Alk⁶ is a C1-C4 alkylene group, L5 is agroup of formula —O—C(═O)—, —C(═O)— or —NR13-C(═O)— and R13 is hydrogenor C1-C4 alkyl, A12 is an unsubstituted or substituted C6-C10 aryl or 5-to 12-membered heterocyclyl group and R′, R″, Y and Z are as definedabove. Where R4 represents an aryl or heterocyclyl group it is typicallyphenyl, benzyl or pyridyl. The aryl or heterocyclyl group may beunsubstituted or substituted as defined above.

R4 preferably represents hydrogen, halogen, phenyl, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, —OR′, CONR′R″, —COR′, —CN, —NO₂, —NR′R″ or —CF₃wherein R′ and R″ are independently hydrogen or C1-C4 alkyl. Morepreferably R4 represents hydrogen, halogen, phenyl, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, —OR′, CONR′R″, —COR′, —CN, —NO₂, —NR′R″ or —CF₃wherein R′ and R″ are independently hydrogen or C1-C4 alkyl. In anotherembodiment R4 represents hydrogen, halogen or C1-C4 alkyl, preferablyhydrogen. Where R4 is capable of being substituted, it is typicallyunsubstituted or substituted with one halogen atom, more preferably itis unsubstituted.

In this embodiment, when R2 is cycloalkyl it is an unsubstitutedcycloalkyl group.

In a further particular embodiment, the present invention provides novelpyrrole derivatives of formula (I) and pharmaceutically oragriculturally acceptable salts thereof. In this embodiment, A1 is abond, a C3-C6 cycloalkyl or an unsubstituted or substituted C6-C10 aryl,5- or 6-membered heterocyclyl or 8- to 10-membered bicyclic heterocyclylgroup. Preferably, A1 represents a C3-C6 cycloalkyl or an unsubstitutedor substituted C6-C10 aryl, 5- or 6-membered heterocyclyl or unsaturated8- to 10-membered bicyclic heterocyclyl group. More preferably, A1represents a phenyl, naphthyl, pyridyl, piperidinyl, benzofuranyl,indolyl, isoquinolinyl or quinolinyl group. Possible substituents on A1are as defined above.

When A1 is a bond, (i) -L1-R1 is not hydrogen, (ii) when R2 isunsubstituted or substituted phenyl and R3 to R5 are all hydrogen,-L1-R1 is not unsubstituted or substituted benzyl or substitutedphenethyl, and (iii) when R6 is hydrogen and R3 to R5 are all hydrogenor chlorine, then none of L1, L3 and L1-R1 represents an unsubstitutedor substituted C1-C4 alkyl group. Preferably, when A1 is a bond, -L1-R1is other than hydrogen, unsubstituted or substituted benzyl, substitutedphenethyl or unsubstituted or substituted C2-C4 alkyl. More preferably,A1 is not a bond.

In this embodiment, when A1 and L1 are both a bond, R1 preferablyrepresents unsubstituted or substituted C1-C8 alkyl, C2-C8 alkenyl,C2-C8 alkynyl, —COR′ or —SO₂(C1-C4 alkyl), or a group -A2, -L2-A2,-L3-A2 or -A2-L3-A3. More preferably, R1 represents an unsubstitutedgroup selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —CO(C1-C4alkyl) and —SO₂(C1-C4 alkyl) or a group -A2, -L2-A2, -L3-A2 or-A2-L3-A3. More preferably, R1 represents a group -A2, -L2-A2, -L3-A2 or-A2-L3-A3. Preferred alkyl, alkenyl and alkynyl groups and substituentson these groups are described above. A2, A3, L2 and L3 are as definedabove.

In this embodiment, R6 is hydrogen.

In this embodiment, when R2 is heterocyclyl, it is not substituted withan aryl or further heterocyclyl group. Preferred substituents on an R2heterocyclyl group are defined above. Preferably, when R2 isheterocyclyl it is not thienyl or benzothienyl, more preferably it isnot thienyl, benzothienyl or pyrazolyl. More preferably, when R2 isheterocyclyl, it is an unsubstituted 5- or 6-membered heterocyclyl ringother than thienyl. More preferably, R2 is not heterocyclyl. Mostpreferred R2 groups are defined above.

When R2 is a substituted C1-C8 alkyl group, the substituent(s) do notinclude —CN or —CO₂H. Preferred substituents on an R2 C1-C8 alkyl groupare defined above. When R2 is substituted phenyl, the substituent(s) donot include nitro. Preferred substituents on an R2 phenyl group aredefined above.

In this embodiment, R4 represents hydrogen, halogen, C1-C8 alkyl, C2-C8alkenyl, C2-C8 alkynyl, —OR′, —CONR′R″, —COR′, —CN, —NO₂, —NR′R″, CF₃,—Y—Z, C6-C10 aryl, or 5- to 12-membered heterocyclyl group, or a groupof formula -Alk⁶-L5-A12, where Alk⁶ is a C1-C4 alkylene group, L5 is agroup of formula —O—C(═O)—, —C(═O)— or —NR13-C(═O)— and R13 is hydrogenor C1-C4 alkyl, A12 is an unsubstituted or substituted C6-C10 aryl or 5-to 12-membered heterocyclyl group and R′, R″, Y and Z are as definedabove. Where R4 represents an aryl or heterocyclyl group it is typicallyphenyl, benzyl or pyridyl. The aryl or heterocyclyl group may beunsubstituted or substituted as defined above.

R4 preferably represents hydrogen, halogen, phenyl, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, —OR′, CONR′R″, —COR′, —CN, —NO₂, —NR′R″ or —CF₃wherein R′ and R″ are independently hydrogen or C1-C4 alkyl. Morepreferably R4 represents hydrogen, halogen, phenyl, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, —OR′, CONR′R″, —COR′, —CN, —NO₂, —NR′R″ or —CF₃wherein R′ and R″ are independently hydrogen or C1-C4 alkyl. In anotherembodiment R4 represents hydrogen, halogen or C1-C4 alkyl, preferablyhydrogen. Where R4 is capable of being substituted, it is typicallyunsubstituted or substituted with one halogen atom, more preferably itis unsubstituted.

In a further aspect of this embodiment, when L1 is a bond, R1 preferablyrepresents hydrogen, unsubstituted or substituted C2-C8 alkenyl, C2-C8alkynyl, —COR′ or —SO₂(C1-C4 alkyl), or a group -A2, -L2-A2, -L3-A2,-A2-L3-A3 or -A4. More preferably, when L1 is a bond, R1 representshydrogen, an unsubstituted group selected from C2-C6 alkenyl, C2-C6alkynyl and —SO₂(C1-C4 alkyl), or a group -A2, -L2-A2, -L3-A2, -A2-L3-A3or -A4. Most preferably, when L1 is a bond, R1 represents hydrogen or agroup -A2, -L2-A2, A2-L3-A3 or A4.

In a preferred aspect of this particular embodiment, when L1 is a bond,R1 preferably represents unsubstituted or substituted C2-C8 alkenyl,C2-C8 alkynyl, —COR′ or —SO₂(C1-C4 alkyl), or a group -A2, -L2-A2,-L3-A2, -A2-L3-A3 or -A4. More preferably, when L1 is a bond, R1represents an unsubstituted group selected from C2-C6 alkenyl, C2-C6alkynyl and —SO₂(C1-C4 alkyl), or a group -A2, -L2-A2, -L3-A2, -A2-L3-A3or -A4. Most preferably, when L1 is a bond, R1 represents -A2, -L2-A2,-A2-L3-A3 or A4.

When L1 is other than a bond, R1 represents hydrogen, unsubstituted orsubstituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —COR′ or—SO₂(C1-C4 alkyl), or a group -A2, -L2-A2, -L3-A2, -A2-L3-A3 or -A4.More preferably, when L1 is other than a bond, R1 represents hydrogen,an unsubstituted group selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, —CO(C1-C4 alkyl) and —SO₂(C1-C4 alkyl), C1-C6 alkyl substitutedwith —OMe or —OEt, or a group -A2, -L2-A2, -L3-A2, -A2-L3-A3 or -A4.Most preferably, when L1 is other than a bond, R1 represents hydrogen, aC1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group,unsubstituted —CO(C1-C4 alkyl), unsubstituted —SO₂(C1-C4 alkyl) or agroup -A2, L2-A2, -L3-A2 or -A2-L3-A3.

Alternatively, when L1 is other than a bond, R1 represents anunsubstituted group selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl and —SO₂(C1-C4 alkyl), or a group -A2, -L2-A2, -L3-A2, -A2-L3-A3or -A4. Most preferably, when L1 is other than a bond, R1 represents aC1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group,unsubstituted —SO₂(C1-C4 alkyl) or a group -A2, L2-A2, -L3-A2 or-A2-L3-A3.

In a further preferred aspect of this embodiment, L1 is a bond, —CH₂—,—NR′—, a C2-C6 alkylene group in which none, one, two or three —CH₂—groups are independently replaced by —O—, —S— or —NR′—, or a 5- to12-membered heterocyclyl group, wherein R′ is as defined above. L1preferably represents a bond, —CH₂—, —NR′—, a 5- to 7-memberedheterocyclyl group or a C2-C6 alkylene group wherein none, one or two—CH₂— groups are independently replaced by —O— or —NR′—, wherein R′ ishydrogen, unsubstituted C1-C4 alkyl or C1-C4 alkyl substituted with anunsubstituted C1-C4 alkoxy group. When L1 represents a 5- to 7-memberedheterocyclyl group, it is preferably as defined above.

In this embodiment, L1 is most preferably —CH₂—, —NR′—, a saturated 5-to 7-membered heterocyclyl group containing one or two nitrogen atoms,or an unsubstituted C2-C6 alkylene group wherein none, one or two —CH₂—groups are independently replaced with —O— or —NR′—, wherein R′ ishydrogen, unsubstituted C1-C4 alkyl or C1-C4 alkyl substituted with anunsubstituted C1-C4 alkoxy group.

Preferred compounds of this embodiment are compounds of formula (IA) asdefined above, or pharmaceutically or agriculturally acceptable saltsthereof, wherein when A1 is a bond, (i) -L1-R1 is not hydrogen, (ii)when R2 is unsubstituted or substituted phenyl and R3 to R5 are allhydrogen, -L1-R1 is not unsubstituted or substituted benzyl orsubstituted phenethyl, and (iii) when R6 is hydrogen and R3 to R5 areall hydrogen or chlorine, then none of L1, L3 and L1-R1 represents anunsubstituted or substituted C1-C4 alkyl group and (iv) when L1 is abond, R1 represents an unsubstituted group selected from C1-C6 alkyl,C2-C6 alkenyl, C2-C6 alkynyl, —CO(C1-C4 alkyl) and —SO₂(C1-C4 alkyl) ora group -A2, -L2-A2, -L3-A2 or -A2-L3-A3.

Typically in this embodiment, L1 represents a bond, —CH₂—, —NR′— asaturated 5- to 7-membered heterocyclyl group containing one or twonitrogen atoms, or an unsubstituted C2-C6 alkylene group wherein none,one or two —CH₂— groups are independently replaced with —O— or —NR′—,wherein R′ is hydrogen, unsubstituted C1-C4 alkyl or C1-C4 alkylsubstituted with an unsubstituted C1-C4 alkoxy group, and wherein theheterocyclyl group is unsubstituted or substituted with an unsubstitutedgroup selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy and halogen. WhenL1 represents an unsubstituted C2-C6 alkylene group wherein none, one ortwo —CH₂— groups are independently replaced with —O— or —NR′—,preferably it is a C4 or C5 alkylene group wherein none, one or two,more preferably one or two, —CH₂— groups are independently replaced with—O— or —NR′— wherein R′ is hydrogen or unsubstituted C1-C4 alkyl.

Specific examples of compounds of formula (I) include:

-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(1-phenyl-1H-pyrrol-2-yl)-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-1-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(2-methyl-7-phenyl-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-6-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(2-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl)-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(7-phenyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-isopropyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-3-(3-morpholin-4-yl-propoxymethyl)-phenyl]-2-oxo-acetamide,-   N-{3-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(3-furan-2-yl-1,5-dimethyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1,5-dimethyl-3-thiophen-2-yl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(3-isopropyl-1,5-dimethyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1,5-dimethyl-3-(tetrahydro-pyran-4-yl)-1H-pyrrol-2-yl]-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-naphthalen-1-yl-2-oxo-acetamide,-   N-{3-(2-Dimethylamino-ethoxymethyl)-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   2-(1,4-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-3-[3-(4-methyl-piperazin-1-yl)-propoxymethyl]-phenyl}-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-isopropyl-1-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{2-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-3-hydroxy-phenyl}-2-oxo-acetamide,-   N-(2,3-Dihydro-benzofuran-4-yl)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{3-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[3-isopropyl-1-(2-methoxy-ethyl)-5-methyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-{2-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-ethoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-[4-(4-pyridin-2-yl-piperazin-1-yl)-phenyl]-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4-methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(6-methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(5-methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-[1-(2-Methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-N-[4-(4-piperazin-1-yl)-phenyl]-acetamide,-   2-[1-(2-Methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-N-{4-[4-(4-methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-[1-(2-Methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-N-{4-[4-(6-methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-[1-(2-Methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-N-{4-[4-(5-methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-Oxo-2-(2-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl)-N-[4-(4-pyridin-2-yl-piperazin-1-yl)-phenyl]-acetamide,-   N-{4-[4-(4-Methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(2-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl)-acetamide,-   N-{4-[4-(6-Methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl},    -2-oxo-2-(2-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl)-acetamide,-   N-{4-[4-(5-Methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(2-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl)-acetamide,-   N-{3-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(2-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl)-acetamide,-   N-{2-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(2-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl)-acetamide,-   2-Oxo-2-(7-phenyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-N-[4-(4-pyridin-2-yl-piperazin-1-yl)-phenyl]-acetamide,-   N-{4-[4-(4-Methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(7-phenyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-acetamide,-   N-{4-[4-(6-Methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(7-phenyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-acetamide,-   N-{4-[4-(5-Methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(7-phenyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-acetamide,-   N-{3-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(7-phenyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-acetamide,-   N-{2-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(7-phenyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-acetamide,-   2-(1,5-Dimethyl-3-thiophen-2-yl-1H-pyrrol-2-yl)-2-oxo-N-[4-(4-pyridin-2-yl-piperazin-1-yl)-phenyl]-acetamide,-   2-(1,5-Dimethyl-3-thiophen-2-yl-1H-pyrrol-2-yl)-N-{4-[4-(4-methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-thiophen-2-yl-1H-pyrrol-2-yl)-N-{4-[4-(5-methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-thiophen-2-yl-1H-pyrrol-2-yl)-N-{4-[4-(6-methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   N-{3-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1,5-dimethyl-3-thiophen-2-yl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{2-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1,5-dimethyl-3-thiophen-2-yl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[4-({2-[(4,6-dimethyl-pyridin-2-yl)-methyl-amino]-ethyl}-methyl-amino)-phenyl]-2-oxo-acetamide,-   N-[4-({2-[(4,6-Dimethyl-pyridin-2-yl)-methyl-amino]-ethyl}-methyl-amino)-phenyl]-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-[4-({2-[(4,6-Dimethyl-pyridin-2-yl)-methyl-amino]-ethyl}-methyl-amino)-phenyl]-2-oxo-2-(7-phenyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-acetamide,-   N-[4-({2-[(4,6-Dimethyl-pyridin-2-yl)-methyl-amino]-ethyl}-methyl-amino)-phenyl]-2-oxo-2-(2-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl)-acetamide,-   N-[4-({2-[(4,6-Dimethyl-pyridin-2-yl)-methyl-amino]-ethyl}-methyl-amino)-phenyl]-2-(1,5-dimethyl-3-thiophen-2-yl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[2-(4,6-dimethyl-pyridin-2-yloxy)-ethylamino]-phenyl}-2-oxo-acetamide,-   N-{4-[2-(4,6-Dimethyl-pyridin-2-yloxy)-ethylamino]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-{4-[2-(4,6-Dimethyl-pyridin-2-yloxy)-ethylamino]-phenyl}-2-oxo-2-(7-phenyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-acetamide,-   N-{-4-[2-(4,6-Dimethyl-pyridin-2-yloxy)-ethylamino]-phenyl}-2-oxo-2-(2-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl)-acetamide,-   N-{4-[2-(4,6-Dimethyl-pyridin-2-yloxy)-ethylamino]-phenyl}-2-(1,5-dimethyl-3-thiophen-2-yl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-{2-[(4,6-dimethyl-pyridin-2-yl)-methyl-amino]-ethoxy}-phenyl)-2-oxo-acetamide,-   N-(4-{2-[(4,6-Dimethyl-pyridin-2-yl)-methyl-amino]-ethoxy}-phenyl)-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-(4-{2-[(4,6-Dimethyl-pyridin-2-yl)-methyl-amino]-ethoxy}-phenyl)-2-oxo-2-(7-phenyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-acetamide,-   N-(4-{2-[(4,6-Dimethyl-pyridin-2-yl)-methyl-amino]-ethoxy}-phenyl)-2-oxo-2-(2-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl)-acetamide,-   N-(4-{2-[(4,6-Dimethyl-pyridin-2-yl)-methyl-amino]-ethoxy}-phenyl)-2-(1,5-dimethyl-3-thiophen-2-yl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[2-(4,6-dimethyl-pyridin-2-yloxy)-ethoxy]-phenyl}-2-oxo-acetamide,-   N-{4-[2-(4,6-Dimethyl-pyridin-2-yloxy)-ethoxy]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-{4-[2-(4,6-Dimethyl-pyridin-2-yloxy)-ethoxy]-phenyl}-2-oxo-2-(7-phenyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-acetamide,-   N-{-4-[2-(4,6-Dimethyl-pyridin-2-yloxy)-ethoxy]-phenyl}-2-oxo-2-(2-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl)-acetamide-   N-{4-[2-(4,6-Dimethyl-pyridin-2-yloxy)-ethoxy]-phenyl}-2-(1,5-dimethyl-3-thiophen-2-yl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-{[2-(4,6-dimethyl-pyridin-2-ylamino)-ethyl]-methyl-amino}-phenyl)-2-oxo-acetamide,-   N-(4-{[2-(4,6-Dimethyl-pyridin-2-ylamino)-ethyl]-methyl-amino}-phenyl)-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-(4-{[2-(4,6-Dimethyl-pyridin-2-ylamino)-ethyl]-methyl-amino}-phenyl)-2-oxo-2-(7-phenyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-acetamide,-   N-(4-{[2-(4,6-Dimethyl-pyridin-2-ylamino)-ethyl]-methyl-amino}-phenyl)-2-oxo-2-(2-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl)-acetamide,-   N-(4-{[2-(4,6-Dimethyl-pyridin-2-ylamino)-ethyl]-methyl-amino}-phenyl)-2-(1,5-dimethyl-3-thiophen-2-yl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[2-(4,6-dimethyl-pyridin-2-ylamino)-ethylamino]-phenyl}-2-oxo-acetamide,-   N-{4-[2-(4,6-Dimethyl-pyridin-2-ylamino)-ethylamino]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-{4-[2-(4,6-Dimethyl-pyridin-2-ylamino)-ethylamino]-phenyl}-2-oxo-2-(7-phenyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-acetamide,-   N-{4-[2-(4,6-Dimethyl-pyridin-2-ylamino)-ethylamino]-phenyl}-2-oxo-2-(2-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl)-acetamide,-   N-{4-[2-(4,6-Dimethyl-pyridin-2-ylamino)-ethylamino]-phenyl}-2-(1,5-dimethyl-3-thiophen-2-yl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-{2-[(4,6-dimethyl-pyridin-2-yl)-methyl-amino]-ethylamino}-phenyl)-2-oxo-acetamide,-   N-(4-{2-[(4,6-Dimethyl-pyridin-2-yl)-methyl-amino]-ethylamino}-phenyl)-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-(4-{2-[(4,6-Dimethyl-pyridin-2-yl)-methyl-amino]-ethylamino}-phenyl)-2-oxo-2-(7-phenyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-acetamide,-   N-(4-{2-[(4,6-Dimethyl-pyridin-2-yl)-methyl-amino]-ethylamino}-phenyl)-2-oxo-2-(2-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl)-acetamide,-   N-(4-{2-[(4,6-Dimethyl-pyridin-2-yl)-methyl-amino]ethylamino}-phenyl)-2-(1,5-dimethyl-3-thiophen-2-yl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-{3-[(4,6-dimethyl-pyridin-2-yl)-methyl-amino]-propyl}-phenyl)-2-oxo-acetamide,-   N-(4-{3-[(4,6-Dimethyl-pyridin-2-yl)-methyl-amino]-propyl}-phenyl)-2-[1-(2-methoxy-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-(4-{3-[(4,6-Dimethyl-pyridin-2-yl)-methyl-amino]-propyl}-phenyl)-2-oxo-2-(7-phenyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-acetamide,-   N-(4-{3-[(4,6-Dimethyl-pyridin-2-yl)-methyl-amino]-propyl}-phenyl)-2-oxo-2-(2-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl)-acetamide,-   N-(4-{3-[(4,6-Dimethyl-pyridin-2-yl)-methyl-amino]-propyl}-phenyl)-2-(1,5-dimethyl-3-thiophen-2-yl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-[1,4]diazepan-1-yl]-phenyl}-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-[1,4]diazepan-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-[1,4]diazepan-1-yl]-phenyl}-2-oxo-2-(7-phenyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-[1,4]diazepan-1-yl]-phenyl}-2-oxo-2-(2-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl)-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-[1,4]diazepan-1-yl]-phenyl}-2-(1,5-dimethyl-3-thiophen-2-yl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[4-({3-[(4,6-dimethyl-pyridin-2-yl)-methyl-amino]-propyl}-methyl-amino)-phenyl]-2-oxo-acetamide,-   N-[4-({3-[(4,6-Dimethyl-pyridin-2-yl)-methyl-amino]-propyl}-methyl-amino)-phenyl]-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-[4-({3-[(4,6-Dimethyl-pyridin-2-yl)-methyl-amino]-propyl}-methyl-amino)-phenyl]-2-oxo-2-(7-phenyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-acetamide,-   N-[4-({3-[(4,6-Dimethyl-pyridin-2-yl)-methyl-amino]-propyl}-methyl-amino)-phenyl]-2-oxo-2-(2-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl)-acetamide,-   N-[4-({3-[(4,6-Dimethyl-pyridin-2-yl)-methyl-amino]-propyl}-methyl-amino)-phenyl]-2-(1,5-dimethyl-3-thiophen-2-yl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4-ethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   N-{4-[4-(4-Ethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-{4-[4-(4-Ethyl-pridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(7-phenyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-acetamide,-   N-{4-[4-(4-Ethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(2-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl)-acetamide,-   2-(1,5-Dimethyl-3-thiophen-2-yl-1H-pyrrol-2-yl)-N-{4-[4-(4-ethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(6-ethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   N-{4-[4-(6-Ethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-{4-[4-(6-Ethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(7-phenyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-acetamide,-   N-{4-[4-(6-Ethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(2-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl)-acetamide,    and-   2-(1,5-Dimethyl-3-thiophen-2-yl-1H-pyrrol-2-yl)-N-{4-[4-(6-ethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,    and    pharmaceutically and agriculturally acceptable salts thereof.

Preferred examples of compounds of formula (I) include:

-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(1-phenyl-1H-pyrrol-2-yl)-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-1-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(2-methyl-7-phenyl-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-6-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(2-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl)-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(7-phenyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-isopropyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-3-(3-morpholin-4-yl-propoxymethyl)-phenyl]-2-oxo-acetamide,-   N-{3-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(3-furan-2-yl-1,5-dimethyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-dimethyl-3-thiophen-2-yl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(3-isopropyl-1,5-dimethyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1,5-dimethyl-3-(tetrahydro-pyran-4-yl)-1H-pyrrol-2-yl]-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-naphthalen-1-yl-2-oxo-acetamide,-   N-{3-(2-Dimethylamino-ethoxymethyl)-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   2-(1,4-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-3-[3-(4-methyl-piperazin-1-yl)-propoxymethyl]-phenyl}-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-isopropyl-1-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{2-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-3-hydroxy-phenyl}-2-oxo-acetamide,-   N-(2,3-Dihydro-benzofuran-4-yl)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{3-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[3-isopropyl-1-(2-methoxy-ethyl)-5-methyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-{2-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,    and-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-ethoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,    and    pharmaceutically and agriculturally acceptable salts thereof.

Further preferred examples of compounds of formula (I) include:

-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(3-methoxy-propyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   2-[1-(2-Methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-N-quinolin-5-yl-acetamide,-   N-Isoquinolin-5-yl-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-quinolin-8-yl-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-quinolin-5-yl-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-pyridin-4-yl-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-ethyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-3-phenyl-1-propyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   2-(1-Butyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-quinolin-3-yl-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-[4-(4-pyridin-2-yl-piperazin-1-yl)-phenyl]-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(6-methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4-methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(2-phenyl-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepin-3-yl)-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(1-phenyl-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepin-3-yl)-acetamide,-   N-Isoquinolin-8-yl-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-isoquinolin-8-yl-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-naphthalen-2-yl-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-methyl-4-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   2-(1-Benzyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[5-(4-methyl-piperazin-1-yl)-naphthalen-1-yl]-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-3-methyl-phenyl}-2-oxo-acetamide,-   (2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-5-methyl-3-phenyl-pyrrol-1-yl)-acetic    acid methyl ester,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-ethyl-1-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[5-ethyl-1-(2-methoxy-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-5-methyl-3-phenyl-pyrrole-1-carboxylic    acid ethyl ester,-   2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-5-methyl-3-phenyl-pyrrole-1-carboxylic    acid methyl ester,-   2-[3-(2-Chloro-phenyl)-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-[4-(2-Chloro-phenyl)-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-[3-(4-Chloro-phenyl)-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-[1-(2-Methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-N-phenyl-1-acetamide,-   (2-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-pyrrol-1-yl)-acetic    acid methyl ester,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-methoxymethyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-methoxymethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-hydroxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   2-[1-(2-Acetylamino-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-hydroxy-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazine-1-yl]-phenyl}-2[1-(2-methoxy-ethyl)-3-thiophen-2-yl-1H-pyrol-2-yl]-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)piperazin-1-yl]-phenyl}-2-[3-isobutyl-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-2-oxo-acetamide,-   2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-5-methyl-3-phenyl-pyrrol-1-yl)-acetic    acid ethyl ester,-   2-[3-(3-Chloro-phenyl)-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-[4-(3-Chloro-phenyl)-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazine-1-yl]-phenyl}-2[1-(2-methoxy-ethyl)-3-thiophen-3-yl-1H-pyrol-2-yl]-2-oxo-acetamide,-   (2-{4-[4-(4,6-Dimethylpyridine-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-3-phenyl    pyrrol-1-yl)acetic acid ester,-   (2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-3-phenyl-pyrrol-1-yl)-acetic    acid methyl ester,-   2-(1-Carbamoylmethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-methyl    carbamoylmethyl-3-phenyl-1-H-pyrrol-2-yl)-2-oxo-acetamide,-   2{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-5-methyl-3-phenyl-pyrrol-1-yl)acetic    acid isopropyl ester,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]phenyl}-2-[5-isopropyl-1-(2-methoxy-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-2-oxo-quinolin-5-yl-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[3-(2-methoxy-ethyl)-5-methyl-1-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   2-[1-(2-Methoxy-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-N-phenyl-1-acetamide,-   2-[1-(2-Methoxy-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-N-propyl-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[3-iso    propyl-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-2-oxo acetamide,-   2-[1-(2-Dimethylamino-ethyl)-3-phenyl-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-[1-(2-Dimethylamino-ethyl)-4-phenyl-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-[1-(2-Dimethylamino-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   (2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-3-thiophen-2-yl-pyrrol-1-yl)-acetic    acid methyl ester,-   (2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-3-iso    propyl-pyrrol-1-yl)-acetic acid methyl ester,-   (2-{4-[4-(4,6-Dimethylpyridine-2-yl)piperazine-1-yl]-phenylamino    oxalyl}-3-isobutyl-pyrrol-1-yl)-acetic acid methyl ester,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(4-fluoro-1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-3-phenyl-1pyridin-2-ylmethyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{2-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-3-phenyl-1-pyridin-3-ylmethyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2,4-fluoro-1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl)    -2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[2-fluoro-4-(4-pyridin-2-yl-piperazin-1-yl)-phenyl]-2-oxo-acetamide,-   N-[2-Fluoro-4-(4-pyridin-2-yl-piperazin-1-yl)-phenyl]-2-[1-(2-methoxy-ethyl-)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-isopropoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   (2-{2-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-5-methyl-3-phenyl-pyrrol-1-yl)-acetic    acid methyl ester,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-(6-pyrrolidin-1-yl-pyridin-3-yl)-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[2-fluoro-4-oxazole-2-yl-phenyl)-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(2-fluoro-4-morpholin-4-yl-phenyl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-3-phenyl-1-pyridin-4-ylmethyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   2-[1-(2-Methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-N-{4-[4-(5-morpholin-4-ylmethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-[3-Cyclobutyl-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperizin-1-yl]-phenyl}-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[2-fluoro-4-(4-isobutyl-piperazin-1-yl)-phenyl]-2-oxoacetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(2-fluoro-4-piperidin-1-yl-phenyl)-2-oxo-acetamide,-   (3-Cyclobutyl-2-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl-]-phenylaminooxalyl}-pyrrol-1-yl)-acetic    acid methyl ester,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{2-fluoro-4-[4-(2-methyl-allyl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   N-{2-Fluoro-4-[4-(2-methyl-allyl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-[2-Fluoro-5-(4-isobutyl-piperazine-1-yl)-phenyl]-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   (2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-2-fluoro-phenylaminooxylyl}-5-methyl-3-phenyl-pyrrol-1-yl)-acetic    acid methyl ester,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(2,2-dimethyl-propyl)-piperazin-1-yl]-2-fluoro-phenyl}-2-oxo-acetamide,-   N-{4-[4-(2,2-Dimethyl-propyl)-piperazin-1-yl]-2-fluoro-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-(2-Fluoro-4-piperidin-1-yl-phenyl)-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-fluoro-4-piperidin-1-yl-phenyl)-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[3-fluoro-4-(4-pyridin-2-yl-piperazin-1-yl)-phenyl]-2-oxo-acetamide,-   N-(2-Fluoro-4-morpholin-4-yl-phenyl)-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[3-fluoro-4(4-isobutyl-piperazin-1-yl)-phenyl]-2-oxo-acetamide,-   N-(3-Fluoro-4-piperidin-1-yl-phenyl)-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(5-morpholin-4-ylmethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-[1-(2-Methoxy-ethyl)-4-phenyl-1H-pyrrol-2-yl]-2-oxo-N-propyl-acetamide,-   (2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-4-phenyl-pyrrol-1-yl)-acetic    acid methyl ester,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-2-fluoro-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperizin-1-yl]-phenyl}-2-[1-methyl-3-phenyl-5-propyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-ethyl-1-methoxymethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-(3-Fluoro-4-morpholin-4-yl-phenyl)-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(5-fluoro-naphthalen-1-yl)-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(1-ethyl-4-fluoro-1H-indol-5-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[5-(2-methoxy-ethyl)-1-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methoxymethyl-1-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   2-(1,5-Bis-methoxymethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazine-1-yl]-phenyl}-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-ethoxymethyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[5-methyl-1-(2-methylsulfanyl-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[5-methyl-1-(2-phenoxy-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   2-(1-Butoxymethyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(3-ethoxy-propyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-1-methylsulfanylmethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethoxymethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-3-phenyl-1-propoxymethyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[5-methyl-3-phenyl-1-(2-propoxy-ethyl)-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(4-methoxy-but-2-enyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(4-methoxy-butyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-(4-piperidin-1-yl-phenyl)-acetamide,-   N-[4-(4-Benzyl-piperazin-1-yl)-phenyl]-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[4-(4-isobutyryl-piperazin-1-yl)-phenyl]-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[5-methyl-1-(2-methyl-oxazol-4-ylmethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-oxazol-2-yl-phenyl)-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-fluoro-4-oxazole-2-yl-phenyl)-2-oxo-acetamide,-   2-[1-(2-Methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-N-(4-oxazol-2-yl-phenyl)-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(1,2-dimethyl-propyl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(2-methoxy-1-methyl-ethyl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(2-furan-2-yl-1-methyl-ethyl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-[4-(5-piperidin-1-ylmethyl-oxazol-2-yl)-phenyl]-acetamide,    and-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-morpholin-4-yl-phenyl)-2-oxo-acetamide,    and pharmaceutically or agriculturally acceptable salts thereof.

Particularly preferred compounds of the invention are

-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-{3-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{2-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{3-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-ethyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-3-phenyl-1-propyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   2-(1-Butyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-[4-(4-pyridin-2-yl-piperazin-1-yl)-phenyl]-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(6-methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4-methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-3-methyl-phenyl}-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-ethyl-1-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-methoxymethyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[2-fluoro-4-(4-pyridin-2-yl-piperazin-1-yl)-phenyl]-2-oxo-acetamide,-   (2-{2-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-5-methyl-3-phenyl-pyrrol-1-yl)-acetic    acid methyl ester,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[2-fluoro-4-(4-isobutyl-piperazin-1-yl)-phenyl]-2-oxoacetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{2-fluoro-4-[4-(2-methyl-allyl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(2,2-dimethyl-propyl)-piperazin-1-yl]-2-fluoro-phenyl}-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[3-fluoro-4-(4-pyridin-2-yl-piperazin-1-yl)-phenyl]-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[3-fluoro-4(4-isobutyl-piperazin-1-yl)-phenyl]-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(5-morpholin-4-ylmethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-2-fluoro-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-ethoxymethyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,    and    pharmaceutically and agriculturally acceptable salts thereof.

2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,and its pharmaceutically and agriculturally acceptable salts, isparticularly preferred.

One embodiment of the invention relates to pyrrole derivatives offormula (IB), which are particularly active against fungi from both theAspergillus and Candida genera and may therefore find use as broadspectrum anti-fungal agents. The pyrrole derivatives of this embodimentare of formula (IB):

wherein A1, L1, n, R1 and R3 to R5 are as defined for formula (I) or(IA) above, and R2 is a group of formula wherein Alk₁ is anunsubstituted or substituted C1-C6 alkylene group, X is a group —O—,—S—, —NR″—, —CO₂—, —CONR″—, —OCO—, —OCONR″— or —SO₂—, and R′ and R″ areindependently selected from hydrogen and unsubstituted or substitutedC1-C4 alkyl, for example unsubstituted or substituted C1-C4 alkyl.

Alk₁ is typically an unsubstituted or substituted C1-C4 alkylene group,for example methylene or ethylene. Where Alk₁ is substituted, ittypically carries one or two, preferably one, substituent selected fromhalogen and further groups of formula —XR′ as defined herein. PreferablyAlk₁ is unsubstituted.

X is typically selected from —O—, —NR″—, —CO₂— and —CONR″—. When X is—CO₂—, R′ is typically a C1-C4 alkyl group.

R′ and R″ typically represent hydrogen or unsubstituted or substitutedmethyl or ethyl. R′ is typically a methyl or ethyl group. R′ and R″ areindependently unsubstituted or substituted, typically with one or two,preferably one, substituent. Suitable substituents are selected fromunsubstituted substituents such as halogen (for example fluorine),hydroxyl, amino, (C1-C4 alkylamino, di(C1-C4 alkyl)amino, —CO₂H and—CO₂(C1-C4 alkyl) and from C1-C4 alkoxy such as methoxy or ethoxy whichare themselves unsubstituted or further substituted with unsubstitutedmethoxy or ethoxy. Preferred substituents are hydroxyl, amino, (C1-C4alkyl)amino, di(C1-C4 alkyl)amino and unsubstituted C1-C4 alkoxy.Preferably R′ and R″ are unsubstituted.

Specific examples of compounds of formula (IB) include:

-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1,5-dimethyl-3-thiophen-2-yl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   (2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-5-methyl-3-phenyl-pyrrol-1-yl)-acetic    acid methyl ester,-   2-[3-(2-Chloro-phenyl)-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-[3-(4-Chloro-phenyl)-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-[1-(2-Methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-N-phenyl-1-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-methoxymethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)piperazin-1-yl]-phenyl}-2-[3-isobutyl-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-2-oxo-acetamide,-   2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-5-methyl-3-phenyl-pyrrol-1-yl)-acetic    acid ethyl ester,-   2-[3-(3-Chloro-phenyl)-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazine-1-yl]-phenyl}-2[1-(2-methoxy-ethyl)-3-thiophen-3-yl-1H-pyrol-2-yl]-2-oxo-acetamide,-   (2-{4-[4-(4,6-Dimethylpyridine-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-3-phenyl    pyrrol-1-yl)acetic acid ester,-   (2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-3-phenyl-pyrrol-1-yl)-acetic    acid methyl ester,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-methyl    carbamoylmethyl-3-phenyl-1-H-pyrrol-2-yl)-2-oxo-acetamide,-   2-[1-(2-Methoxy-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-N-phenyl-1-acetamide,-   2-[1-(2-Dimethylamino-ethyl)-3-phenyl-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-[1-(2-Dimethylamino-ethyl)-4-phenyl-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-[1-(2-Dimethylamino-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   (2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-3-thiophen-2-yl-pyrrol-1-yl)-acetic    acid methyl ester,-   (2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-3-iso    propyl-pyrrol-1-yl)-acetic acid methyl ester,-   (2-{4-[4-(4,6-Dimethylpyridine-2-yl)piperazine-1-yl]-phenylamino    oxalyl}-3-isobutyl-pyrrol-1-yl)-acetic acid methyl ester,-   2-[1-(2-Methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-N-{4-[-(5-morpholin-4-ylmethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-[3-Cyclobutyl-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperizin-1-yl]-phenyl}-2-oxo-acetamide,-   N-{2-Fluoro-4-[4-(2-methyl-allyl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-{4-[4-(2,2-Dimethyl-propyl)-piperazin-1-yl]-2-fluoro-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,    and-   N-(2-Fluoro-4-piperidin-1-yl-phenyl)-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,    and    pharmaceutically and agriculturally acceptable salts thereof.

Compounds of the invention containing one or more chiral centre may beused in enantiomerically or diastereoisomerically pure form, or in theform of a mixture of isomers. For the avoidance of doubt, the compoundsof the invention can, if desired, be used in the form of solvates.Further, for the avoidance of doubt, the compounds of the invention maybe used in any tautomeric form.

As used herein, a pharmaceutically acceptable salt is a salt with apharmaceutically acceptable acid or base. Pharmaceutically acceptableacids include both inorganic acids such as hydrochloric, sulphuric,phosphoric, diphosphoric, hydrobromic, hydroiodic or nitric acid andorganic acids such as citric, fumaric, maleic, malic, ascorbic,succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic,benzenesulphonic, p-toluenesulphonic acid, formic, acetic, propionic,glycolic, lactic, pyruvic, oxalic, salicylic, trichloroacetic, picric,trifluoroacetic, cinnamic, pamoic, malonic, mandelic, bismethylenesalicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic,palmitic, EDTA, p-aminobenzoic or glutamic acid, sulfates, nitrates,phosphates, perchlorates, borates, acetates, benzoates,hydroxynaphthoates, glycerophosphates or ketoglutarates. Furtherexamples of pharmaceutically acceptable inorganic or organic acidaddition salts include the pharmaceutically acceptable salts listed inJournal of Pharmaceutical Science, 66, 2 (1977) which are known to theskilled artisan. Pharmaceutically acceptable bases include alkali metal(e.g. sodium or potassium) and alkali earth metal (e.g. calcium ormagnesium) hydroxides and organic bases such as alkyl amines, aralkylamines and heterocyclic amines, lysine, guanidine, diethanolamine andcholine.

Also intended as pharmaceutically acceptable acid addition salts are thehydrates which the present compounds are able to form.

The acid addition salts may be obtained as the direct products ofcompound synthesis. In the alternative, the free base may be dissolvedin a suitable solvent containing the appropriate acid, and the saltisolated by evaporating the solvent or otherwise separating the salt andsolvent.

The compounds of this invention may form solvates with standard lowmolecular weight solvents using methods known to the skilled artisan.

The present invention also provides prodrugs of the compounds of theinvention. A prodrug is an analogue of a compound of the invention whichwill be converted in vivo to the desired active compound. Examples ofsuitable prodrugs include compounds of formula (I) which have beenmodified at a carboxylic acid group to form an ester, or at hydroxylgroup to form an ester or carbamate. Other suitable methods will beknown to those skilled in the art. Further suitable prodrugs includethose in which a nitrogen atom of a compound of formula (I) isquaternised by addition of an ester or alkyl ester group. For example,the nitrogen atom of an amine group or heterocyclyl ring on asubstituent R1 or R5 may be quaternised by addition of a —CH₂—O—CORgroup, wherein R is typically methyl or tert-butyl.

Suitable salts of the compounds of the invention include those mentionedherein as examples of pharmaceutically and agriculturally acceptablesalts.

The compounds of the invention may be synthesised by reacting a compoundof formula (II), wherein R2, R3, R4 and R5 are as hereinbefore defined,with a compound of formula (III), wherein R6, A1, n, L1 and R1 are ashereinbefore defined. Typically the reaction takes place in the presenceof an organic solvent and a base. Preferably the solvent isdichloromethane or tetrahydrofuran and the base is triethylamine orpyridine. Typically the reaction is carried out at 0° C. initially whilethe reagents are added and then stirred at room temperature until thereaction is complete. Compounds of formula (III) are typically availablefrom commercial sources or can be prepared by known methods. Details ofthe synthesis of certain compounds of formula (III) are providedhereinafter.

A compound of formula (II) may be prepared by reacting a compound offormula (IV), wherein R2, R3, R4 and R5 are as hereinbefore defined,with preferably oxalyl chloride. Typically the reaction takes place inan organic solvent. Preferably, the solvent is dichloromethane.Typically, the reaction is carried out at 0° C. initially while thereagents are added and then stirred at room temperature until thereaction is complete.

The experimental section provides specific synthetic examples, and othercompounds of the invention can be prepared by analogy with thesespecific synthetic examples and with reference to the general syntheticmethodology discussed above. Some further general synthetic schemes andspecific aniline-intermediate preparation summaries are as follows:

Preparation of β-Ketoesters:

Solvent: acetonitrileBase: triethylamineAdditional reagent: magnesium chloridePreparation of Oximes:

Reagent: sodium nitriteSolvent: acetic acidPreparation of Pyrrole Diesters:

Reagents: zinc powder, sodium acetateSolvent: acetic acidTemperature: 60-75° C.Pyrrole N-alkylation:

Reagents/solvents: sodium hydride, THF, 0° C. to room temperature;sodium hydride, DMF, 0° C. to 90° C.; potassium carbonate, acetonitrile,reflux.Ester Hydrolysis:

Reagents: sodium or potassium hydroxide, water/ethanol or water/methanolmixtures, reflux temperature.Decarboxylation:

Solvent: ethanolamineTemperature: 175-180° C.Primary Amines:There are a large number of ways of preparing primary alkyl amines andmany examples are commercially available. Two of the most commonexamples of primary amine synthesis are:1. The catalytic reduction of commercially available nitriles and nitrocompounds to the corresponding amine:

2. Gabriel synthesis

Exemplary anilines required for preparation of a number of preferredcompounds of the invention could be prepared according to the followingsequences of reactions:

4-(4-Pyridin-2-yl-piperazin-1-yl)-phenylamine

From 1-(4-nitro-phenyl)-piperazine and 2-chloropyridine, by heating inDMSO to give 1-(4-nitro-phenyl)-4-pyridin-2-yl-piperazine then catalytichydrogenation over Raney nickel in methanol.

4-[4-(4-Methyl-pyridin-2-yl)-piperazin-1-yl]-phenylamine

From 1-(4-nitro-phenyl)-piperazine and 2-chloro-4-methylpyridine, byheating in diglyme to give1-(4-methyl-pyridin-2-yl)-4-(4-nitro-phenyl)-piperazine then catalytichydrogenation over Raney nickel in methanol.

4-[4-(6-Methyl-pyridin-2-yl)-piperazin-1-yl]-phenylamine

From 1-(4-nitro-phenyl)-piperazine and 2-chloro-6-methylpyridine, byheating in the presence of palladium (II) acetate,2-dicyclohexylphospino-2-(N,N′-dimethyl amino)biphenyl and caesiumcarbonate in a mixture of toluene and THF to give1-(6-methyl-pyridin-2-yl)-4-(4-nitro-phenyl)-piperazine then catalytichydrogenation over Raney nickel in methanol.

4-[4-(5-Methyl-pyridin-2-yl)-piperazin-1-yl]-phenylamine

From 1-(4-nitro-phenyl)-piperazine and 2-chloro-5-methylpyridine, in thesame manner as the preparation of4-[4-(6-methyl-pyridin-2-yl)-piperazin-1-yl]-phenylamine.

4-[4-(4-Ethyl-pyridin-2-yl)-piperazin-1-yl]-phenylamine

From 2-amino-4-ethylpyridine by treatment with sodium nitrite inhydrochloric acid in the presence of sodium chloride to afford2-chloro-4-ethylpyridine, then in the same manner as4-[4-(6-methyl-pyridin-2-yl)-piperazin-1-yl]-phenylamine.

4-[4-(6-Ethyl-pyridin-2-yl)-piperazin-1-yl]-phenylamine

From 2-amino-6-ethylpyridine, in the same manner as4-[4-(4-ethyl-pyridin-2-yl)-piperazin-1-yl]-phenylamine.

N-{2-[(4,6-Dimethyl-pyridin-2-yl)-methyl-amino]-ethyl}-N-methyl-benzene-1,4-diamine

From 1-chloro-4-nitrobenzene by heating in neat ethylene diamine to giveN*1*-(4-nitro-phenyl)-ethane-1,2-diamine, followed by treatment withtrifluoro-methanesulfonic acid 4,6-dimethyl-pyridin-2-yl ester (itselfprepared according to J. Org. Chem., 63, 10048-51 (1998) using pyridineas base) in diglyme at reflux to affordN-(4,6-dimethyl-pyridin-2-yl)-N′-(4-nitro-phenyl)-ethane-1,2-diamine.Dimethylation with methyl iodide in THF in the presence of sodiumhydride followed by catalytic hydrogenation over Raney nickel inmethanol gives the required aniline.

N-[2-(4,6-Dimethyl-pyridin-2-yloxy)-ethyl]-benzene-1,4-diamine

From 2-chloro-4,6-dimethylpyridine by treatment with ethanolamine andsodium hydroxide in a mixture of water and dioxane to afford2-(4,6-dimethyl-pyridin-2-yloxy)-ethylamine, followed by heating with1-fluoro-4-nitrobenzene in ethanol to give[2-(4,6-dimethyl-pyridin-2-yloxy)-ethyl]-(4-nitro-phenyl)-amine. Thefree amine is protected as a trifluoroacetamide by treatment withtrifluoroacetic anhydride and sodium hydride in THF then the nitro groupis reduced with zinc powder in the presence of ammonium chloride inethanol. Following coupling with the appropriately-selected acidchloride, a final treatment with lithium hydroxide in methanol removesthe trifluoroacetamide to give the final compound described.

[2-(4-Amino-phenoxy)-ethyl]-(4,6-dimethyl-pyridin-2-yl)-methyl-amine

From 4-nitrophenol by etherification with bromoacetic acid in thepresence of sodium hydride in THF, acid chloride formation with thionylchloride and catalytic DMF and amide formation with2-amino-4,6-dimethylpyridine in triethylamine and chloroform to giveN-(4,6-dimethyl-pyridin-2-yl)-2-(4-nitro-phenoxy)-acetamide. The amideis the reduced with borane-dimethylsulfide in THF at reflux, theresulting amine methylated with methyl iodide in the presence of sodiumhydride in THF, and finally catalytic hydrogenation over Raney nickel inmethanol gives the required aniline.

4-[2-(4,6-Dimethyl-pyridin-2-yloxy)-ethoxy]-phenylamine

From 4-nitrophenol by etherification with 1,2-dibromoethane, withpotassium carbonate as the base in 2-butanone to give1-(2-bromo-ethoxy)-4-nitro-benzene, followed by O-alkylation of2-hydroxy-4,6-dimethylpyridine using potassium carbonate in DMF to give2,4-Dimethyl-6-[2-(4-nitro-phenoxy)-ethoxy]-pyridine. Reduction of thenitro group with tin (II) chloride in a mixture of ethanol and ethylacetate gives the required aniline.

N-[2-(4,6-Dimethyl-pyridin-2-ylamino)-ethyl]-N-methyl-benzene-1,4-diamine

From 1-fluoro-4-nitrobenzene by heating with glycine at reflux in amixture of aqueous sodium bicarbonate and dioxane to give(4-nitro-phenylamino)-acetic acid, followed by treatment withformaldehyde and formic acid at reflux to give[methyl-(4-nitro-phenyl)-amino]-acetic acid. Treatment with thionylchloride and catalytic DMF to give the acid chloride followed by amideformation with 2-amino-4,6-dimethylpyridine in triethylamine andchloroform givesN-(4,6-dimethyl-pyridin-2-yl)-2-(4-nitro-phenylamino)-acetamide. Theamide is the reduced with borane-dimethylsulfide in THF at reflux thencatalytic hydrogenation over Raney nickel in methanol gives the requiredaniline.

N-[2-(4,6-Dimethyl-pyridin-2-ylamino)-ethyl]-benzene-1,4-diamine

From 4-nitroaniline by treatment with ethyl oxalyl chloride intriethylamine and THF to give N-(4-nitro-phenyl)-oxalamic acid ethylester, followed by aminolysis with 2-amino-4,6-dimethylpyridine intriethylamine at reflux to affordN-(4,6-dimethyl-pyridin-2-yl)-N-(4-nitro-phenyl)-oxalamide. The amidesare then reduced with borane-dimethylsulfide in THF at reflux, the freeamine is protected as a trifluoroacetamide by treatment withtrifluoroacetic anhydride and sodium hydride in THF then the nitro groupis reduced with zinc powder in the presence of ammonium chloride inethanol. Following coupling with the appropriately-selected acidchloride, a final treatment with lithium hydroxide in methanol removesthe trifluoroacetamide to give the final compound described.

N-{2-[(4,6-Dimethyl-pyridin-2-yl)-methyl-amino]-ethyl}-benzene-1,4-diamine

From (4-nitro-phenylamino)-acetic acid (prepared as described above) bytreatment with trifluoroacetic anhydride and sodium hydride in THF togive [(4-nitro-phenyl)-(2,2,2-trifluoro-acetyl)-amino]-acetic acidfollowed by acid chloride formation with thionyl chloride in chloroformand coupling with (4,6-dimethyl-pyridin-2-yl)-methyl-amine to yieldN-{[(4,6-dimethyl-pyridin-2-yl)-methyl-carbamoyl]-methyl}-2,2,2-trifluoro-N-(4-nitro-phenyl)-acetamide.Treatment with lithium hydroxide in methanol removes thetrifluoroacetamide, then the amide is reduced withborane-dimethylsulfide in THF at reflux to giveN-(4,6-Dimethyl-pyridin-2-yl)-N-methyl-N′-(4-nitro-phenyl)-ethane-1,2-diamine.Catalytic hydrogenation over Raney nickel in methanol gives the requiredaniline.

[3-(4-Amino-phenyl)-propyl]-(4,6-dimethyl-pyridin-2-yl)-methyl-amine

Alkylation of diethyl malonate with 4-nitrobenzyl bromide using sodiumhydride in THF, followed by ester hydrolysis with sodium hydroxide inwater and ethanol, then heating the resulting diacid to its meltingpoint causing decarboxylation gives 3-(4-nitro-phenyl)-propionic acid.Conversion to the acid chloride with thionyl chloride in DCM andcoupling with 2-amino-4,6-dimethylpyridine affordsN-(4,6-dimethyl-pyridin-2-yl)-3-(4-nitro-phenyl)-propionamide. Amidereduction with borane-dimethylsulfide in THF at reflux, methylation ofthe resulting amine with methyl iodide and sodium hydride in THF andfinally catalytic hydrogenation over Raney nickel in methanol gives therequired aniline.

4-[4-(4,6-Dimethyl-pyridin-2-yl)-[1,4]diazepan-1-yl]-phenylamine

From 1-chloro-4-nitrobenzene and [1,4]diazepane (homopiperazine) byheating in n-butanol at reflux to give1-(4-nitro-phenyl)-[1,4]diazepane, followed by reaction with2-chloro-4,6-dimethylpyridine by heating in the presence of palladium(II) acetate, 2-dicyclohexylphospino-2-(N,N′-dimethyl amino)biphenyl andcaesium carbonate in a mixture of toluene and THF to give1-(4,6-dimethyl-pyridin-2-yl)-4-(4-nitro-phenyl)-[1,4]diazepane, andfinally reduction with tin (II) chloride in a mixture of ethanol andethyl acetate gives the required aniline.

N-{3-[(4,6-Dimethyl-pyridin-2-yl)-methyl-amino]-propyl}-N-methyl-benzene-1,4-diamine

From methyl-(4-nitro-phenyl)-amine and acrylic acid by heating withcatalytic sulfuric acid to give3-[methyl-(4-nitro-phenyl)-amino]-propionic acid, acid chlorideformation with thionyl chloride in DCM and coupling with(4,6-dimethyl-pyridin-2-yl)-methyl-amine to affordN-(4,6-dimethyl-pyridin-2-yl)-N-methyl-3-[methyl-(4-nitro-phenyl)-amino]-propionamide.Amide reduction with borane-dimethylsulfide in THF at reflux andcatalytic hydrogenation over Raney nickel in methanol gives the requiredaniline.

All of the starting materials referred to in the reactions describedabove are available from commercial sources or can be prepared byanalogy with known methods.

In one embodiment, the present invention provides combinations of thepyrrole derivative of formula (I), (IA) or (IB) or a pharmaceuticallyacceptable salt thereof, with a further antifungal agent. Thus, thepyrrole derivative of formula (I), (IA), (IB) or pharmaceuticallyacceptable salt thereof (also referred to herein as the first antifungalagent) is present in the combinations, compositions and products of theinvention with a second antifungal agent. The second antifungal agentused in the invention can be any suitable antifungal agent that theskilled person would judge to be useful in the circumstances.Particularly suitable classes of antifungal agents include azoles,polyenes, purine nucleotide inhibitors, pyrimidine nucleotideinhibitors, mannan inhibitors, protein elongation factor inhibitors,chitin synthase inhibitors, Beta-glucan synthase inhibitors,echinocandins, allylamines, anti-HSP90 antibodies,bactericidal/permeability inducing protein products and polyoxins. Othersuitable antifungal agents which do not fall within the classes aboveinclude the compounds AN2690, AN2718 and icofungipen.

Preferred azoles are clotrimazole, econazole, bifonazole, butoconazole,fenticonazole, fluconazole, isoconazole, itraconazole, ketoconazole,miconazole, oxiconazole, sertaconazole, sulconazole, tioconazole,isavuconazole, ravuconazole, posaconazole, terconazole and voriconazole.Preferred echinocandins are anidulafungin, caspofungin and micafungin.Preferred allylamines are terbinafine, butenafine, amorolfine andnaftifine. Preferred polyenes are amphotericin B and nystatin. Apreferred example of a purine or pyrimidine nucleotide inhibitor isflucytosine. A preferred mannan inhibitor is pradamicin. A preferredprotein elongation factor inhibitor is sordarin and analogues thereof. Apreferred polyoxin is nikkomycin Z.

Particularly preferred second antifungal agents are caspofungin,micafungin, amphotericin B, voriconazole, posaconazole, fluconazole anditraconazole.

Examples of preferred combinations of the invention are compounds offormula (IA) and their pharmaceutically acceptable salts as definedabove with a second antifungal agent selected from caspofungin,micafungin, amphotericin B, voriconazole, posaconazole, fluconazole anditraconazole. Further preferred combinations of the invention arecombinations of (i) compounds of formula (Ia) and pharmaceuticallyacceptable salts thereof wherein:

A1 represents phenyl, which may be unsubstituted or substituted with oneor more substituents selected from unsubstituted C1-C4 alkyl, C1-C4alkyl substituted with an unsubstituted C1-C4 alkoxy group,unsubstituted C1-C4 alkoxy, —CO₂H and halogen, preferably A1 isunsubstituted or substituted with one group selected from F, C1 andmethyl, most preferably A1 is unsubstituted;

n represents one;

L1 represents an unsubstituted, saturated 5- to 7-membered heterocyclylgroup containing two nitrogen atoms, the heterocycle being attached toA1 and to R1 via a nitrogen atom, preferably L1 represents piperazinyl;

R1 represents unsubstituted C1-C6 alkyl, unsubstituted C2-C6 alkenyl, ora group -A2, —CH₂-A2 or -A2-CH₂-A3;

A2 and A3 independently represent phenyl or a 5- or 6-memberedheterocyclyl group, wherein A2 and A3 are unsubstituted or substitutedwith one, two or three substituents selected from the unsubstitutedsubstituents halogen, —COCF₃, —OCONR′R″ and —NR′R″, and from C1-C4 alkyland C1-C4 alkoxy groups which are unsubstituted or substituted with —OH,—OMe, —OEt or —O(C1-C4 alkyl)-O(C1-C2 alkyl), wherein R′ and R″ areindependently selected from hydrogen, unsubstituted C1-C4 alkyl andC1-C4 alkyl substituted with a hydroxyl or unsubstituted C1-C4 alkoxygroup;

R5 represents unsubstituted phenyl;

R2 represents hydrogen, or C1-C4 alkyl or C2-C4 alkenyl, each of whichmay be unsubstituted or substituted with —OMe, —OEt, —OPr, —OBu,—OCH₂CH₂OMe, —SMe, hydroxy, di(C1-C4 alkyl)amino, —COO(C1-C4 alkyl),—CONR′R″ or —NR′CO(C1-C4 alkyl) where R′ and R″ are the same ordifferent and represent hydrogen or unsubstituted C1-C4 alkyl; or R2represents a group (C1-C4) alkyl-A5, wherein none or one —CH₂— groupsare independently replaced by —O— and wherein A5 represents phenyl,pyridinyl or oxazolyl, each of which is unsubstituted or substitutedwith one or two substituents selected from halogen, C1-C4 alkyl andC1-C4 alkoxy; and

R3 represents hydrogen or C1-C4 alkyl which is unsubstituted orsubstituted with —OMe or —OEt;

with (ii) a second antifungal agent selected from caspofungin,micafungin, amphotericin B, voriconazole, posaconazole, fluconazole anditraconazole.

In a preferred aspect of this embodiment, in the compounds of formula(IA), A1 is a phenyl group which is unsubstituted or substituted with F,Cl or methyl, preferably A1 is unsubstituted phenyl; L1 is piperazinyland is linked to A1 and R1 via a nitrogen atom; and R1 is unsubstitutedC1-C6 alkyl, unsubstituted C2-C6 alkenyl, or piperidinyl, wherein thepiperidinyl group is unsubstituted or substituted with one, two or threesubstituents selected from unsubstituted C1-C4 alkyl groups. Morepreferably, R1 is piperidinyl which is substituted with two methylgroups.

In a further preferred aspect of this embodiment, in the compounds offormula (IA), R2 and R3 are independently selected from hydrogen andunsubstituted C1-C4 alkyl groups, preferably methyl.

In a further preferred aspect of this embodiment, the compound offormula (IA) is2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,

-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-{3-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{2-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{3-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-ethyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-3-phenyl-1-propyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   2-(1-Butyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-[4-(4-pyridin-2-yl-piperazin-1-yl)-phenyl]-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(6-methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4-methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-3-methyl-phenyl}-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-ethyl-1-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-methoxymethyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[2-fluoro-4-(4-pyridin-2-yl-piperazin-1-yl)-phenyl]-2-oxo-acetamide,-   (2-{2-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-5-methyl-3-phenyl-pyrrol-1-yl)-acetic    acid methyl ester,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[2-fluoro-4-(4-isobutyl-piperazin-1-yl)-phenyl]-2-oxoacetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{2-fluoro-4-[4-(2-methyl-allyl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(2,2-dimethyl-propyl)-piperazin-1-yl]-2-fluoro-phenyl}-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[3-fluoro-4-(4-pyridin-2-yl-piperazin-1-yl)-phenyl]-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[3-fluoro-4(4-isobutyl-piperazin-1-yl)-phenyl]-2-oxo-acetamide,-   2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(5-morpholin-4-ylmethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-2-fluoro-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,    or-   N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-ethoxymethyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,    or    a pharmaceutically acceptable salt thereof.

The most preferred combinations of the invention include combinations of2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamideor a pharmaceutically acceptable salt thereof, with a second antifungalagent selected from caspofungin, micafungin, amphotericin B,voriconazole, posaconazole, fluconazole and itraconazole.

The compounds of the invention have antifungal activity. Accordingly,they may be used in a method of treating a subject suffering from orsusceptible to a fungal disease, which method comprises administering tosaid subject an effective amount of a pyrrole derivative of formula (I),(IA) or (IB) or a pharmaceutically acceptable salt thereof. Thecompounds may be used in combination with a second antifungal agent, asdesired.

Preferably, the fungal disease comprises an infection by a fungus, forexample an Ascomycete. Preferably, the fungal disease comprises aninfection by an organism selected from the genera Absidia; Acremonium;Alternaria; Aspergillus; Bipolaris; Blastomyces; Blumeria; Candida;Cladosporium; Coccidioides; Colletotrichium; Cryptococcus; Curvularia;Encephalitozoon; Epicoccum; Epidermophyton; Exophiala; Exserohilum;Fusarium; Histoplasma; Leptosphaeria; Microsporum; Mycosphaerella;Neurospora, Paecilomyces; Penicillium; Phytophthora; Plasmopara;Pneumocystis; Pyricularia; Pythium; Puccinia; Rhizoctonia; Rhizomucor;Scedosporium; Scopulariopsis; Trichophyton; Trichosporon; and Ustilago.

Preferably, the fungal disease comprises an infection by an organism ofthe genus Aspergillus or Candida.

Preferably, the fungal disease comprises an infection by an organismselected from the species Absidia corymbifera; Acremonium spp;Alternaria alternata; Aspergillus flavus; Aspergillus fumigatus;Aspergillus nidulans; Aspergillus niger; Aspergillus parasiticus;Aspergillus terreus; Bipolaris spp; Blastomyces dermatitidis; Blumeriagraminis; Candida albicans; Candida glabrata; Candida krusei; Candidaparapsilosis; Candida tropicalis; Cladosporium cladosporoides;Cladosporium herbarium; Coccidioides immitis; Coccidioides posadasii;Curvularia lunata; Colletotrichium trifolii; Cryptococcus neoformans;Encephalitozoon cuniculi; Epicoccum nigrum; Epidermophyton fioccosum;Exophiala spp; Exserohilum rostratum; Fusarium graminarium; Fusariumsolani; Fusarium sporotrichoides; Histoplasma capsulatum; Leptosphaerianodorum; Microsporum canis; Mycosphaerella graminicola; Paecilomyceslilanicus; Paecilomyces varioti; Penicillium chrysogenum; Phytophthoracapsici; Phytophthora infestans; Plasmopara viticola; Pneumocystisfiroveci; Puccinia coronata; Puccinia graminis; Pyricularia oryzae;Pythium ultimum; Rhizoctonia solani; Rhizomucor spp; Rhizopus spp;Scedosporium apiospermum; Scedosporium prolificans; Scopulariopsisbrevicaulis; Trichophyton mentagrophytes; Trichophyton interdigitale;Trichophyton rubrum; Trichosporon asahii; Trichosporon beigelii; andUstilago maydis.

Preferably, the fungal disease comprises an infection by Aspergillusfumigatus.

Examples of fungal diseases, which can be prevented or treated using thecompounds of the invention, include both systemic and superficialinfections. The fungal diseases include invasive fungal diseases causedby Aspergillus and Candida species such as aspergillosis or candidiasis,but also local forms of these infections. The compounds of the inventionare particularly useful against diseases caused by Aspergillus species,for which a fungicidal drug is required which has lower toxicity thanamphotericin. The invention also provides for the treatment ofdermatological infections.

In one embodiment, the compounds of the invention are for use in theprevention or treatment of a disease caused by Aspergillus species. In afurther embodiment of the invention, the compounds of the invention arepyrrole derivatives of formula (IB) or pharmaceutically acceptable saltsthereof, these compounds being for use in preventing or treatingdiseases caused by Candida species. The compounds of formula (IB) orpharmaceutically acceptable salts thereof are therefore particularlyuseful in the prevention or treatment of diseases caused by Aspergillusspecies and diseases caused by Candida species.

The diseases caused by Aspergillus species include diseases caused by A.fumigatus, A. flavus, A. terreus and A. niger.

The diseases cause by Candida species include diseases caused by C.albicans, C. glabrata, C. krusei, C. tropicalis and C. parapsillosis.

Examples of systemic infections which might be prevented or treatedusing the compounds of the invention include: systemic candidiasis;pulmonary aspergillosis, e.g. in immunosuppressed patients such as bonemarrow recipients or AIDS patients; systemic aspergillosis; cryptococcalmeningitis; rhinocerebral mucomycosis; blastomycosis; histoplasmosis;coccidiomycosis; paracoccidiomycosis; lobomycosis; sporotrichosis;chromoblastomycosis; phaeohyphomycosis; zygomycosis; cryptococcosis anddisseminated sporotrichosis.

Examples of superficial infections, which can be prevented or treatedusing the compounds of the invention, include: ring worm; athlete'sfoot; tinea unguium (nail infection); candidiasis of skin, mouth orvagina; and chronic mucocutaneous candidiasis.

Examples of diseases or conditions which are caused by fungi or wherefungi exacerbate an allergic response, and which can be prevented ortreated using the compounds of the invention, include allergicbronchopulmonary asthma (ABPA); asthma, rhinosinusitis and sinusitis.

The present invention includes a pharmaceutical composition comprising acompound according to the invention and a pharmaceutically acceptablecarrier or diluent. Said pharmaceutical composition typically containsup to 85 wt % of a compound of the invention. More typically, itcontains up to 50 wt % of a compound of the invention. Preferredpharmaceutical compositions are sterile and pyrogen free. Where acompound of the invention can exist as optical isomers, thepharmaceutical compositions provided by the invention typically containa substantially pure optical isomer.

In one embodiment, the composition additionally comprises a secondantifungal agent. In this embodiment, the pyrrole and second antifungalagent need not be present in admixture in a single composition. However,the pyrrole and second antifungal agent are preferably formulated forsimultaneous or successive administration.

The compounds, combinations, compositions and products of the inventionmay be administered in a variety of dosage forms. Thus, they can beadministered orally, for example as tablets, troches, lozenges, aqueousor oily suspensions, dispersible powders or granules. The compounds,combinations, compositions and products of the invention may also beadministered parenterally, either subcutaneously, intravenously,intramuscularly, intrasternally, transdermally or by infusiontechniques. The compounds, combinations, compositions and products mayalso be administered as suppositories. The compounds, combinations,compositions and products may be administered by inhalation in the formof an aerosol via an inhaler or nebuliser.

A compound of the invention, and optionally a second antifungal agent,is typically formulated for administration with a pharmaceuticallyacceptable carrier or diluent. For example, solid oral forms maycontain, together with the active compound, solubilising agents, e.g.cyclodextrins or modified cyclodextrins; diluents, e.g. lactose,dextrose, saccharose, cellulose, corn starch or potato starch;lubricants, e.g. silica, talc, stearic acid, magnesium or calciumstearate, and/or polyethylene glycols; binding agents; e.g. starches,arabic gums, gelatin, methylcellulose, carboxymethylcellulose orpolyvinyl pyrrolidone; disaggregating agents, e.g. starch, alginic acid,alginates or sodium starch glycolate; effervescing mixtures; dyestuffs;sweeteners; wetting agents, such as lecithin, polysorbates,laurylsulphates; and, in general, non-toxic and pharmacologicallyinactive substances used in pharmaceutical formulations. Suchpharmaceutical preparations may be manufactured in known manner, forexample, by means of mixing, granulating, tabletting, sugar-coating, orfilm coating processes.

Liquid dispersions for oral administration may be solutions, syrups,emulsions and suspensions. The solutions may contain solubilising agentse.g. cyclodextrins or modified cyclodextrins. The syrups may contain ascarriers, for example, saccharose or saccharose with glycerine and/ormannitol and/or sorbitol.

Suspensions and emulsions may contain as carrier, for example a naturalgum, agar, sodium alginate, pectin, methylcellulose,carboxymethylcellulose, or polyvinyl alcohol. The suspensions orsolutions for intramuscular injections may contain, together with theactive compound, a pharmaceutically acceptable carrier, e.g. sterilewater, olive oil, ethyl oleate, glycols, e.g. propylene glycol;solubilising agents, e.g. cyclodextrins or modified cyclodextrins, andif desired, a suitable amount of lidocaine hydrochloride.

Solutions for intravenous or infusions may contain as carrier, forexample, sterile water and solubilising agents, e.g. cyclodextrins ormodified cyclodextrins or preferably they may be in the form of sterile,aqueous, isotonic saline solutions.

Nanoformulations are also envisaged.

A therapeutically effective amount of a compound of the invention isadministered to a patient. A typical daily dose is up to 200 mg, e.g. upto 100 mg or up to 50 mg per kg of body weight, for example from 0.001to 200 or 0.001 to 50 mg per kg of body weight, according to theactivity of the specific compound or combination of specific antifungalagents used, the age, weight and conditions of the subject to betreated, the type and severity of the disease and the frequency androute of administration. Preferably, daily dosage levels are up to 200mg, e.g. up to 150 mg, up to 100 mg, up to 50 mg or up to 40 mg per kgof body weight. Daily dosage levels are for example at least 1 mg, atleast 2 mg or at least 5 mg per kg of body weight. In one embodiment thedaily dosage level is from 0.05 mg to 2 g, preferably from 0.1 mg to 10mg. Where a combination is administered, the compound of the inventionis typically administered in an amount of at least 0.05 mg, preferablyat least 0.1 mg, 2 mg or at least 5 mg. A preferred upper limit on theamount of compound of the invention administered is typically 200 mg,e.g. 100 mg, 50 mg or 25 mg. The second antifungal agent is typicallyadministered at or below the standard dose used for that drug. Anadvantage of the combinations of the present invention is that knownantifungal agents may be administered in lower doses than are currentlyused, resulting in a reduction in toxic effects. The compound,combination or composition of the invention is typically administered tothe patient in a non-toxic amount.

The present invention also provides a method of controlling a fungaldisease of a plant, which comprises applying to the locus of the plant apyrrole derivative of formula (I), (IA) or (IB) or an agriculturallyacceptable salt thereof, and optionally a second antifungal agent.

The compounds, combinations, compositions and products of the inventionmay, for example, be applied to the seeds of the plants, to the medium(e.g. soil or water) in which the plants are grown, or to the foliage ofthe plants.

The compounds, combinations, compositions and products of the inventionare preferably used in the treatment or prevention of fungal diseases.Examples of fungal diseases of plants which can be controlled using thecompounds of the invention include fungal diseases caused by thefollowing plant pathogens: Blumeria graminis; Colletotrichium Fusariumgraminearium; Fusarium solani; Fusarium sporotrichoides; Leptosphaerianodoruin; Magnaporthe grisea; Mycosphaerella graminicola; Neurosporacrassa; Phytophthora capsici; Phytophthora infestans; Plasmoparaviticola; Puccinia coronata; Puccinia graminis; Pyricularia oryzae;Pythium ultimum; Rhizoctonia solani; Trichophyton rubrum; and Ustilagomaydis.

The present invention includes a composition comprising a compound ofthe invention, or an agriculturally acceptable salt thereof, and anagriculturally acceptable carrier or diluent. In one embodiment of theinvention, the composition further comprises a second antifungal agent.Said agricultural composition typically contains up to 85 wt % of acompound of the invention. More typically, it contains up to 50 wt % ofa compound of the invention. When used in an agricultural composition,the skilled person will readily be able to determine suitable levels ofadministration. As examples, the antifungal agent(s) can be used at alevel of from 5 g to 10 kg per hectare, for example from 10 g to 5 kgper hectare, for example from 100 g to 2 kg per hectare.

Suitable agriculturally acceptable salts include salts withagriculturally acceptable acids, both inorganic acids such ashydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitricacid and organic acids such as citric, fumaric, maleic, malic, ascorbic,succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic,benzenesulphonic or p-toluenesulphonic acid. Salts may also be formedwith agriculturally acceptable bases such as alkali metal (e.g. sodiumor potassium) and alkaline earth metal (e.g. calcium or magnesium)hydroxides and organic bases such as alkyl amines, aralkyl amines orheterocyclic amines. A preferred agriculturally acceptable salt is thehydrochloride salt.

The compounds of the invention, and optional second antifungal agents,may be applied in combination with inert carriers or diluents, as inaqueous sprays, granules and dust formulations in accordance withestablished practice in the art. An aqueous spray is usually prepared bymixing a wettable powder or emulsifiable concentrate formulation of acompound of the invention with a relatively large amount of water toform a dispersion.

Wettable powders may comprise an intimate, finely divided mixture of acompound of the invention, an inert solid carrier and a surface-activeagent. The inert solid carrier is usually chosen from among theattapulgite clays, the kaolin clays, the montmorillonite clays, thediatomaceous earths, finely divided silica and purified silicates.Effective surfactants, which have wetting, penetrating and dispersingability are usually present in a wettable powder formulation inproportions of from 0.5 to 10 percent by weight. Among the surfaceactive agents commonly used for this purpose are the sulfonated lignins,naphthalenesulfonates and condensed naphthalenesulfonates,alkylbenzenesulfonates, alkyl sulfates and non-ionic surfactants such asproducts of condensation of ethylene oxide with alkylphenols.

Emulsifiable concentrates may comprise a solution of a compound of theinvention in a liquid carrier which is a mixture of a water-immisciblesolvent and a surfactant, including an emulsifier. Useful solventsinclude aromatic hydrocarbon solvents such as the xylenes,alkylnaphthalenes, petroleum distillates, terpene solvents,ether-alcohols and organic ester solvents. Suitable emulsifiers,dispersing and wetting agents may be selected from the same classes ofproducts which are employed in formulating wettable powders.

The fungicide formulations desirably contain from 0.1 percent to 95percent by weight of the compound of the invention, or in the case of acombination of antifungal agents the total weight of antifungal agent,and from 0.1 to 75 percent of an inert carrier or surfactant. The directapplication to plant seeds prior to planting may be accomplished in someinstances by mixing either a powdered solid compound of the invention ora dust formulation with seed to obtain a substantially uniform coatingwhich is very thin and represents only one or two percent by weight orless, based on the weight of the seed. In some instances, however, anon-phytotoxic solvent such as methanol is conveniently employed as acarrier to facilitate the uniform distribution of the compound of theinvention on the surface of the seed.

When a compound of the invention, or in the case of a combination ofantifungal agents one of the antifungal agents used, is to be applied tothe soil, as for pre-emergence protection, granular formulations ordusts are sometimes more convenient than sprays. A typical granularformulation comprises a compound of the invention dispersed on an inertcarrier such as coarsely ground clay, or clay which has been convertedto granules by treatment of a rolling bed of the powdered material witha small amount of liquid in a granulating drum. In the usual process forpreparing granular formulations, a solution of the active compound issprayed on the granules while they are being agitated in a suitablemixing apparatus, after which the granules are dried with a current ofair during continued agitation. Dust formulations customarily employessentially the same inert diluents as wettable powders and granules,but are well-mixed in powder form and do not usually containemulsifiers. Dusts may contain some surface active agents to facilitateuniform distribution of the active ingredient in the formulation and toimprove the uniformity and adhesion of the dust coating on seeds andplants. The colloidal dispersion of dust formulations in the air isusually prevented by incorporation of a minor amount of an oily or waxymaterial in the formulation to cause agglomeration of colloidal sizeparticles. In this way the dust may be applied to seeds or plantswithout generation of an air-polluting aerosol.

The following examples illustrate the invention but are not intended tolimit the scope of the invention. In this regard, it is important tounderstand that the particular assays used in the Examples section aredesigned only to provide an indication of anti-fungal activity. Thereare many assays available to determine such activity, and a negativeresult in any one particular assay is therefore not determinative.

EXAMPLES Reference Example 1 3-Methoxypropionyl chloride

Thionyl chloride (7.48 g, 64.46 mmol) was added to a solution of2-methoxy-propionic acid (6.0 g, 57.69 mmol) in chloroform (50 mL) andrefluxed for 2 h. Chloroform was then added and excess thionyl chlorideremoved in vacuo to afford (6.0 g, 82%) of 3-methoxypropionyl chlorideas a colourless liquid.

Reference Example 2 Ethyl 3-(2-furyl)-3-oxo-propanoate

Triethylamine (11.7 mL, 84.3 mmol) was added dropwise to a suspension ofpotassium ethyl malonate (13.4 g, 78.5 mmol) in acetonitrile (80 mL) at10° C., followed by portionwise addition of anhydrous magnesium chloride(9.12 g, 95.8 mmol). The reaction mixture was warmed to room temperatureand stirred for 2.5 h. The resulting white slurry was cooled to 0° C.and furan-2-carbonyl chloride (5.0 g, 38.3 mmol) in acetonitrile (20 mL)was added dropwise over a period of 20 min. The mixture was allowed tostir at ambient temperature overnight. The solvent was evaporated invacuo and the residue was azeotroped with toluene (10 mL) then dissolvedin toluene, cooled to between 0 and 5° C. and acidified with 13% aqueoushydrochloric acid (50 mL). After stirring for 15 min the aqueous phasewas separated and the organic phase was washed with 13% aqueoushydrochloric acid (2×50 mL) followed by water (2×25 mL) and concentratedin vacuo to afford the crude compound. Purification by flash columnchromatography over silica gel (100-200 mesh) using 5% ethyl acetate inpetroleum ether as eluent afforded ethyl 3-(2-furyl)-3-oxo-propanoate(5.01 g, 72%) as a pale yellow liquid.

Reference Examples 3 to 8

The compounds set out below were prepared in a manner analogous toReference Example 2:

Reference Example Compound 3 Ethyl 3-oxo-3-(2-thienyl)propanoate 4 Ethyl4-methyl-3-oxo-pentanoate 5 Ethyl3-oxo-3-tetrahydropyran-4-yl-propanoate 6 Ethyl 3-oxopentanoate 7 Ethyl3-oxohexanoate 8 Ethyl 5-methoxy-3-oxo-pentanoate

Reference Example 9 Ethyl-2-hydroxyimino-3-oxo-3-phenyl-propanoate

A solution of sodium nitrite (56.5 g, 0.815 mol) in water (400 mL) wasadded to a solution of ethyl benzoyl acetate (120 g, 0.625 mol) inglacial acetic acid (300 mL) at 0-10° C. over a period of 2 h. Theproduct started precipitating during the course of addition and thereaction mixture was warmed to room temperature and stirred for 30 min.Water (2.5 L) was added and the mixture was stirred for a further 30 minand then filtered under suction. The solid was washed with water (20mL), petroleum ether (200 mL) and then dissolved in chloroform (700 mL).The filtrate was extracted with chloroform (2×100 mL) and the combinedorganic phase was washed with water (2×200 mL), brine solution (2×250mL), dried over anhydrous sodium sulfate and concentrated in vacuo toafford ethyl-2-hydroxyimino-3-oxo-3-phenyl-propanoate (122.5 g, 88%).

Reference Example 10 to 14

The compounds set out below were prepared in a manner analogous toReference Example 9:

Reference Example Compound 10 Ethyl3-(2-furyl)-2-hydroxyimino-3-oxo-propanoate 11 Ethyl2-hydroxyimino-3-oxo-3-(2-thienyl)propanoate 12 Ethyl2-hydroxyimino-4-methyl-3-oxo-pentanoate 13 Ethyl2-hydroxyimino-3-oxo-3-tetrahydropyran-4-yl- propanoate 14 Ethyl2-hydroxyimino-5-methoxy-3-oxo-pentanoate

Reference Example 15 Diethyl5-methyl-3-phenyl-1H-pyrrole-2,4-dicarboxylate

A mixture of ethyl acetoacetate (72.5 g, 0.56 mol), zinc dust (98 g,1.51 mol) and anhydrous sodium acetate (102 g, 1.21 mol) in glacialacetic acid (110 mL) was heated to 60° C.Ethyl-2-hydroxyimino-3-oxo-3-phenyl-propanoate (110 g, 0.5 mol) wasadded as a solution (some precipitation on standing) in glacial aceticacid (550 mL) in 3 portions with vigorous stirring over a period of 1 h.The temperature increased to 90° C. during the addition and the reactionwas then maintained at 60-75° C. for 3 h. Additional zinc dust (49 g,0.75 mol) was added over 15 min, again causing a temperature rise, andthen the reaction mixture was then stirred at 60 to 75° C. for 1 h.After cooling to room temperature the mixture was filtered and thefiltrate was evaporated in vacuo to give a residue which was azeotropedwith toluene (2×200 mL) to remove residual acetic acid. Water (2 L) andethyl acetate (300 mL) were added to the residue and the mixture wasstirred until two clear phases were obtained. The organic phase wasseparated and the aqueous phase extracted with ethyl acetate (2×200 mL).The combined organic phases were washed successively with water (2×250mL), saturated bicarbonate solution (2×250 mL), water (2×100 mL), brine(2×100 mL), dried over anhydrous sodium sulfate and then concentrated togive a gummy residue. A mixture of dichloromethane and petroleum ether(175 mL; 1:6) was added to the solid and it was stirred for 15 min. Theresulting free-flowing solid was filtered off and washed with chilledpetroleum ether (100 mL) to afford diethyl5-methyl-3-phenyl-1H-pyrrole-2,4-dicarboxylate (85 g, 57%) as anoff-white solid.

Reference Examples 16 to 24

The compounds set out below were prepared in a manner analogous toReference Example 15:

Reference Example Compound 16 2-Ethyl 4-methyl3-(2-furyl)-5-methyl-1H-pyrrole-2,4- dicarboxylate 17 Diethyl5-methyl-3-(2-thienyl)-1H-pyrrole-2,4-dicarboxylate 18 2-Ethyl 4-methyl3-isopropyl-5-methyl-1H-pyrrole-2,4- dicarboxylate 19 2-Ethyl 4-methyl5-methyl-3-tetrahydropyran-4-yl-1H-pyrrole- 2,4-dicarboxylate 20 Diethyl5-isopropyl-3-phenyl-1H-pyrrole-2,4-dicarboxylate 21 Diethyl5-ethyl-3-phenyl-1H-pyrrole-2,4-dicarboxylate 22 Diethyl3-(2-methoxyethyl)-5-methyl-1H-pyrrole-2,4- dicarboxylate 23 Diethyl3-phenyl-5-propyl-lH-pyrrole-2,4-dicarboxylate 24 Diethyl5-(2-methoxyethyl)-3-phenyl-1H-pyrrole-2,4- dicarboxylate

Reference Example 25 Ethyl 4-methyl-3-phenyl-1H-pyrrole-2-carboxylate

1,8-Diazabicyclo[5.4.0]undec-7-ene (3.70 g, 24.6 mmol) was addeddropwise to a stirred solution of ethyl isocyanoacetate (1.50 g, 13.3mmol) and 2-nitro-3-phenyl-2-propene (2.0 g, 12.3 mmol) in a mixture oftetrahydrofuran (15 mL) and iso-propanol (5 mL) at between 10 and 20° C.The reaction mixture was stirred at room temperature for 4 h. Excesstetrahydrofuran was removed in vacuo, water (15 mL) was added to theresidue and the mixture was extracted with diethyl ether (3×25 mL). Thecombined organic phases were washed with brine (2×15 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure toafford ethyl 4-methyl-3-phenyl-1H-pyrrole-2-carboxylate (2.5 g, 90%) asan oil.

Reference Example 26Diethyl-1,5-dimethyl-3-phenyl-pyrrole-2,4-dicarboxylate

A solution of diethyl 5-methyl-3-phenyl-1H-pyrrole-2,4-dicarboxylate (85g, 0.28 mol) in dry tetrahydrofuran (240 mL) was added to a suspensionof sodium hydride (60% w/w; 17 g, 0.425 mol) in dry tetrahydrofuran (200mL) at 0° C. over 45 min. The mixture was warmed to room temperature andstirred for 1 h before cooling back to 0 C. Methyl iodide (71 mL, 1.13mol) was added dropwise over 30 min and the reaction mixture and thenstirred at room temperature for 18 h. The mixture was quenched withice-water (100 mL) and concentrated in vacuo to remove volatileorganics. The aqueous phase was decanted off and the residual solid wasextracted with dichloromethane (350 mL). The aqueous phase was extractedwith dichloromethane (2×100 mL) and the combined extracts were washedsuccessively with water (2×200 mL), brine (2×100 mL), dried overanhydrous sodium sulfate and concentrated to afford diethyl1,5-dimethyl-3-phenyl-pyrrole-2,4-dicarboxylate (80 g, 90%) as a yellowsolid.

Reference Examples 27 to 34

The compounds set out below were prepared in a manner analogous toReference Example 26:

Reference Example Compound 27 2-Ethyl 4-methyl3-(2-furyl)-1,5-dimethyl-pyrrole-2,4- dicarboxylate 28 Diethyl1,5-dimethyl-3-(2-thienyl)pyrrole-2,4-dicarboxylate 29 2-Ethyl 4-methyl3-isopropyl-1,5-dimethyl-pyrrole-2,4- dicarboxylate 30 2-Ethyl 4-methyl1,5-dimethyl-3-tetrahydropyran-4-yl-pyrrole- 2,4-dicarboxylate 31 Ethyl1,4-dimethyl-3-phenyl-pyrrole-2-carboxylate 32 Diethyl5-isopropyl-1-methyl-3-phenyl-pyrrole-2,4- dicarboxylate 33 Diethyl1-methyl-3-phenyl-5-propyl-pyrrole-2,4-dicarboxylate 342-(Methoxymethyl)-1-methyl-4-phenyl-pyrrole

Reference Example 35 Diethyl3-isopropyl-1-(2-methoxyethyl)-5-methyl-pyrrole-2,4-dicarboxylate

Sodium hydride (55%; 555 mg, 12.7 mmol) was added to a solution of2-ethyl 4-methyl 3-isopropyl-5-methyl-1H-pyrrole-2,4-dicarboxylate (1.8g, 6.74 mmol) in dry dimethylformamide (10 mL) at 0-5° C. and stirredfor 30 min. 1-Bromo-2-methoxy-ethane (1.0 mL, 10.1 mmol) was addeddropwise to the mixture which was stirred at 90° C. for 2 h. Additionalsodium hydride (55%; 275 mg, 6.37 mmol) was added followed by1-bromo-2-methoxy-ethane (1.0 mL, 10.1 mmol) and stirring continued at90° C. for 5 h. The reaction mixture was cooled to room temperature,quenched with ice water and extracted with ethyl acetate (2×30 mL). Thecombined organic phases were washed with water (2×50 mL), brine (50 mL),dried over anhydrous sodium sulfate and concentrated in vacuo to afforddiethyl3-isopropyl-1-(2-methoxyethyl)-5-methyl-pyrrole-2,4-dicarboxylate (2.2g, 100%).

Reference Examples 36 to 43

The compounds set out below were prepared in a manner analogous toReference Example 35:

Reference Example Compound 36 Diethyl1-ethyl-5-methyl-3-phenyl-pyrrole-2,4-dicarboxylate 37 Diethyl5-methyl-3-phenyl-1-propyl-pyrrole-2,4-dicarboxylate 38 Diethyl1-butyl-5-methyl-3-phenyl-pyrrole-2,4-dicarboxylate 39 Ethyl1-methyl-4-phenyl-pyrrole-2-carboxylate 40 Diethyl1-benzyl-5-methyl-3-phenyl-pyrrole-2,4-dicarboxylate 41 Methyl2-(2-methyl-4-phenyl-pyrrol-1-yl)acetate 42 Diethyl1-(2-methoxyethyl)-5-methyl-3-phenyl-pyrrole-2,4- dicarboxylate 43Diethyl 5-methyl-1-(2-phenoxyethyl)-3-phenyl-pyrrole-2,4- dicarboxylate

Reference Example 44 1-Ethoxy-2-iodo-ethane

Toluene-4-sulfonic acid 2-ethoxy-ethyl ester (prepared according toCrowley et. al., J. Chem. Soc., 1957, 2931-2934; 3.5 g, 14.3 mmol) wasadded to a solution of sodium iodide (4.30 g, 28.7 mmol) in acetone (30mL) and heated at reflux overnight. Acetone was evaporated from thereaction mixture and ether was added. The mixture was filtered and thefiltrate was concentrated in vacuo to afford 1-ethoxy-2-iodo-ethane (1.5g, 52%).

Reference Example 45 Diethyl1-(2-ethoxyethyl)-5-methyl-3-phenyl-pyrrole-2,4-dicarboxylate

Potassium carbonate (1.82 g, 13.3 mmol) was added to a solution ofdiethyl 5-methyl-3-phenyl-1H-pyrrole-2,4-dicarboxylate (1.0 g, 3.32mmol) and 1-ethoxy-2-iodo-ethane (1.98 g, 9.96 mmol) in acetonitrile (20mL) and the mixture heated at reflux for 72 h. The inorganic salts werefiltered off and the filtrate was concentrated in vacuo to afforddiethyl 1-(2-ethoxyethyl)-5-methyl-3-phenyl-pyrrole-2,4-dicarboxylate(1.25 g, quantitative).

Reference Examples 46 to 49

The compounds set out below were prepared in a manner analogous toReference Example 45:

Reference Example Compound 46 Diethyl1-(3-chloropropyl)-5-methyl-3-phenyl-pyrrole-2,4- dicarboxylate 47Diethyl 5-isopropyl-1-(2-methoxyethyl)-3-phenyl-pyrrole-2,4-dicarboxylate 48 1-Benzyl-4-isobutyl-piperazine 49 tert-Butyl4-(2-methylallyl)piperazine-1-carboxylate

Reference Example 50 Ethyl 2-cyano-4-methyl-pent-2-enoate

A solution of piperidine (0.3 mL, 3.04 mmol) in acetic acid (3 mL) wasadded to a solution of ethyl cyano acetate (10 g, 88.50 mmol) andisobutyraldehyde (9.35 g, 0.13 mol) in acetic acid at room temperature.The reaction mixture was allowed to stand for 24 h at room temperature,then diluted with water (50 mL) and extracted with ether (3×50 mL). Thecombined ether layers were washed with saturated bicarbonate solution,water, and brine and the organics were dried over anhydrous sodiumsulfate and concentrated under reduced pressure to give the crudecompound. Purification by vacuum distillation (95° C. at 0.1 mm Hg)afforded ethyl 2-cyano-4-methyl-pent-2-enoate (6.5 g, 30%) as a liquid.

Reference Example 51 2-Isopropylbutanedinitrile

A solution of potassium cyanide (5.81 g, 89.52 mmol) in water (12 mL)was added to a solution of ethyl 2-cyano-4-methyl-pent-2-enoate (6.5 g,38.92 mmol) in ethanol (20 mL) at room temperature and the reactionmixture was stirred overnight. The resulting mixture was refluxed for 2h and then cooled to room temperature. The ethanol was evaporated andthe residue dissolved in dichloromethane. The dichloromethane layer waswashed with water and brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to give 2-isopropylbutanedinitrile(3.5 g, 74%) as a liquid.

Reference Example 52 3-Isopropyl-1H-pyrrole

20% Diisobutyl aluminium hydride in toluene (62 mL, 74.59 mmol) wasadded to a solution of 2-isopropylbutanedinitrile (3.5 g, 28.69 mmol) inbenzene (25 mL) at 0° C. The reaction mixture was warmed to roomtemperature and stirred for 3 h. The reaction mixture was quenched with2M sodium dihydrogen phosphate solution (200 mL), refluxed for 1 h thencooled to room temperature. Ether (50 mL) was added and the un-dissolvedsalts were filtered and 15% aq sodium chloride solution was added to thefiltrate. The ether layer was separated, washed with water, brinesolution and dried over anhydrous sodium sulfate. The organics wereconcentrated under reduced pressure to give the crude compound which waspurified by vacuum distillation (100° C. at 0.15 mm Hg) to afford3-isopropyl-1H-pyrrole (350 mg, 11%) as a liquid.

Reference Example 53 Ethyl1-(2-methoxyethyl)-4-phenyl-pyrrole-2-carboxylate

Potassium tert-butoxide (780 mg, 6.96 mmol) was added in three portionsover a period of 10 min to a stirred solution of ethyl4-phenyl-1H-pyrrole-2-carboxylate (1.0 g, 4.63 mmol) indimethylsulfoxide (10 mL) at 10° C. and maintained at this temperaturefor 30 min. A solution of 1-bromo-2-methoxy-ethane (770 mg, 5.50 mmol)in dimethylsulfoxide (2 mL) was added dropwise to the reaction mixtureat 10° C. and then stirred for 2 h at room temperature. The reactionmixture was poured into ice water (25 mL) and the aqueous layerextracted with diethyl ether (3×20 mL). The combined organic layer waswashed with water, brine (2×20 mL), dried over anhydrous sodium sulphateand concentrated under reduced pressure to afford ethyl1-(2-methoxyethyl)-4-phenyl-pyrrole-2-carboxylate (1.15 g, 91%) as anoil.

Reference Examples 54 to 77

The compounds set out below were prepared in a manner analogous toReference Example 53:

Reference Example Compound 54 Diethyl5-ethyl-1-methyl-3-phenyl-pyrrole-2,4-dicarboxylate 55 Diethyl5-ethyl-1-(2-methoxyethyl)-3-phenyl-pyrrole-2,4- dicarboxylate 56 Ethyl4-(2-chlorophenyl)-1-(2-methoxyethyl)pyrrole-2- carboxylate 574-(4-Chlorophenyl)-1-(2-methoxyethyl)pyrrole-2-carboxylic acid 58 Methyl2-pyrrol-1-ylacetate 59 1-(2-Methoxyethyl)-3-(2-thienyl)pyrrole 60 Ethyl4-isobutyl-1-(2-methoxyethyl)pyrrole-3-carboxylate 615-(3-Phenylpyrrol-1-yl)pentanenitrile 62 tert-Butyl2-(2-methyl-4-phenyl-pyrrol-1-yl)acetate 63 Ethyl4-(3-chlorophenyl)-1-(2-methoxyethyl)pyrrole-2- carboxylate 641-(2-Methoxyethyl)-3-(3-thienyl)pyrrole 65 tert-Butyl2-(3-phenylpyrrol-1-yl)acetate 66 3-Isopropyl-1-(2-methoxyethyl)pyrrole67 N,N-dimethyl-2-(3-phenylpyrrol-1-yl)ethanamine 68N,N-dimethyl-2-(2-methyl-4-phenyl-pyrrol-1-yl)ethanamine 69 tert-Butyl2-[3-(2-thienyl)pyrrol-1-yl]acetate 70 tert-Butyl2-(3-isobutylpyrrol-1-yl)acetate 71 Diethyl5-methyl-3-phenyl-1-(2-pyridylmethyl)pyrrole-2,4- dicarboxylate 723-[(2-Methyl-4-phenyl-pyrrol-1-yl)methyl]pyridine 733-Bromo-1-(2-methoxyethyl)-2-methyl-4-phenyl-pyrrole 741-(2-Isopropoxyethyl)-2-methyl-4-phenyl-pyrrole 75 Diethyl5-methyl-3-phenyl-1-(4-pyridylmethyl)pyrrole-2,4- dicarboxylate 763-Cyclobutyl-1-(2-methoxyethyl)pyrrole 77 tert-Butyl2-(3-cyclobutylpyrrol-1-yl)acetate

Reference Example 78 Diethyl5-methyl-1-(2-methylsulfanylethyl)-3-phenyl-pyrrole-2,4-dicarboxylate

Potassium t-butoxide (224 mg, 2.00 mmol) was added to a solution ofdiethyl 5-methyl-3-phenyl-1H-pyrrole-2,4-dicarboxylate (500 mg, 1.66mmol) in dry dimethylsulfoxide (10 mL) at 10° C. over 5 min. Thereaction mixture was allowed to warm to ambient temperature and stirredfor 30 min before cooling again to 10° C.1-Chloro-2-methylsulfanyl-ethane (200 mg, 1.81 mmol) was added slowlyand the reaction mixture then stirred at ambient temperature for 72 h.Saturated aqueous ammonium chloride was added and the mixture extractedwith diethyl ether. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate and concentrated in vacuo to affordthe crude product. Purification by flash column chromatography over100-200 mesh silica gel by eluting with 5%-7% ethyl acetate in petroleumether afforded diethyl5-methyl-1-(2-methylsulfanylethyl)-3-phenyl-pyrrole-2,4-dicarboxylate(420 mg, 68%) as a liquid.

Reference Example 79

The compound set out below was prepared in a manner analogous toReference Example 78:

Reference Example Compound 79 Diethyl5-methyl-1-(methylsulfanylmethyl)-3-phenyl-pyrrole- 2,4-dicarboxylate

Reference Example 80 Diethyl5-ethyl-1-(methoxymethyl)-3-phenyl-pyrrole-2,4-dicarboxylate

Sodium hydride (50% in mineral oil; 220 mg, 4.76 mmol) was added to asolution of diethyl 5-methyl-3-phenyl-1H-pyrrole-2,4-dicarboxylate (1 g,3.18 mmol) in dimethylformamide (15 mL) at 0° C. and then the mixturestirred for 30 min at ambient temperature. The mixture was cooled to 0°C. and chloro-methoxy-methane (0.3 ml, 3.8 mmol) was added and the wholerefluxed for 6 h. The reaction mixture was cooled, washed with water(2×25 ml) and extracted with ethyl acetate (4×25 ml). The combined ethylacetate extracts were washed with water (2×25 ml), brine (25 ml), driedover anhydrous sodium sulphate and concentrated to afford diethyl5-ethyl-1-(methoxymethyl)-3-phenyl-pyrrole-2,4-dicarboxylate (1 g, 88%)as a pale yellow liquid.

Reference Examples 81

The compound set out below was prepared in a manner analogous toReference Example 80:

Reference Example Compound 81 Methyl1-(methoxymethyl)-4-phenyl-pyrrole-2-carboxylate

Reference Example 82 Diethyl5-(2-methoxyethyl)-1-methyl-3-phenyl-pyrrole-2,4-dicarboxylate

Potassium t-butoxide (0.51 g, 4.62 mmol) was added to a solution ofdiethyl 5-(2-methoxyethyl)-3-phenyl-1H-pyrrol-2,4-dicarboxylate (0.8 g,2.31 mmol) in dry dimethylsulfoxide (15 mL) and stirred for 30 min atambient temperature. To the reaction mixture was added methyl iodide(0.49 g, 3.47 mmol) and the reaction was stirred for a further 1 h.Saturated aqueous ammonium chloride was added and the mixture extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous sodium sulfate and concentrated in vacuo to afford diethyl542-methoxyethyl)-1-methyl-3-phenyl-pyrrole-2,4-dicarboxylate (0.6 g,72%) as a solid.

Reference Example 83 1,2-Bis(methoxymethyl)-4-phenyl-pyrrole

Sodium hydride (400 mg 1.83 mmol, 60%) was added to a solution of(1-methoxymethyl-4-phenyl-1H-pyrrol-2-yl)-methanol (420 mg, 2.08 mmol)in tetrahydrofuran (15 mL) at 0° C. and stirred for a further 15 min.Methyl iodide (517 mg, 3.66 mmol) was added and the reaction mixturestirred for 12 h. The mixture was poured into saturated aqueous ammoniumchloride and extracted with ethyl acetate (2×50 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate and concentrated in vacuo to afford1,2-bis(methoxymethyl)-4-phenyl-pyrrole (300 mg, 72%) as a brown liquid.

Reference Examples 84 to 85

The compounds set out below were prepared in a manner analogous toReference Example 83:

Reference Example Compound 841-(3-Ethoxypropyl)-2-methyl-4-phenyl-pyrrole 852-Methyl-4-phenyl-1-(2-propoxyethyl)pyrrole

Reference Example 86 3-(2-Thienyl)prop-2-enoic acid

Piperidine (2.45 g, 0.056 mol) was added drop wise over a period of 10min to a stirred solution of thiophene-2-carbaldehyde (4.00 g, 0.036mol) and malonic acid (1.00 g, 0.18 mol) in pyridine (40 mL) at 0° C.and the resulting reaction mixture was refluxed for 2 h. The reactionmixture was poured into 2N HCl (100 mL) and the precipitated solidfiltered. The aqueous layer was extracted with ethyl acetate and theorganic layer was washed with brine solution, dried over anhydroussodium sulphate and concentrated under reduced pressure to afford3-(2-thienyl)prop-2-enoic acid (5.00 g, 92%) as a solid.

Reference Examples 87 to 89

The compounds set out below were prepared in a manner analogous toReference Example 86:

Reference Example Compound 87 5-Methylhex-2-enoic acid 883-(3-Thienyl)prop-2-enoic acid 89 4-Methylpent-2-enoic acid

Reference Example 90 Ethyl (3-(2-thienyl)prop-2-enoate

A mixture of 3-(2-thienyl)prop-2-enoic acid (4.00 g, 25.94 mmol),thionyl chloride (6.20 mL, 77.90 mmol) and ethanol (45 mL) were refluxedfor 3 h. Excess ethanol was removed in vacuo, then chloroform was addedto the residue. The organic phase was washed with saturated sodiumbicarbonate solution, water, brine and dried over anhydrous sodiumsulfate. The organics were concentrated under reduced pressure to givethe crude compound which was purified by column chromatography oversilica gel (100-200 mesh) using 5% ethyl acetate in pet ether as eluentto afford ethyl (3-(2-thienyl)prop-2-enoate (2.70 g, 57%) as an oil.

Reference Examples 91 to 96

The compounds set out below were prepared in a manner analogous toReference Example 90:

Reference Example Compound 91 Ethyl 5-methylhex-2-enoate 92 Ethyl2-(2-methyl-4-phenyl-pyrrol-1-yl)acetate 93 Ethyl3-(3-thienyl)prop-2-enoate 94 Methyl 2-(3-phenylpyrrol-1-yl)acetate 95Methyl 2-[3-(2-thienyl)pyrrol-1-yl]acetate 96 Methyl4-methylpent-2-enoate

Reference Example 97 Ethyl 4-(2-thienyl)-1H-pyrrole-3-carboxylate

A solution of ethyl (3-(2-thienyl)prop-2-enoate (2.50 g, 13.70 mmol) andtoluenesulfonylmethyl isocyanide (2.90 g, 14.90 mmol) indimethylsulfoxide:diethyl ether (12.50 mL:20 mL) was added drop wiseover a period of 15 min to a stirred solution of 60% sodium hydride inmineral oil (760 mg, 18.30 mmol) in diethyl ether (20 mL) at 10° C.Stirring was continued for 3 h at room temperature and the reactionmixture was quenched with saturated ammonium chloride solution andextracted with diethyl ether. The organic layer was washed with brine,dried over anhydrous sodium sulfate and concentrated under reducedpressure to give crude compound which was purified by columnchromatography over silica gel (100-200 mesh) using 18% ethyl acetate inpet ether as eluent to afford 4-thiophene-2-yl-1H-pyrrole-3-carboxylicacid ethyl ester (100 mg, 42%) as a solid.

Reference Examples 98 to 100

The compounds set out below were prepared in a manner analogous toReference Example 97:

Reference Example Compound 98 Ethyl 4-isobutyl-1H-pyrrole-3-carboxylate99 Ethyl 4-(3-thienyl)-1H-pyrrole-3-carboxylate 100 Ethyl4-isopropyl-1H-pyrrole-3-carboxylate

Reference Example 101 Diethyl3-(2-methoxyethyl)-5-methyl-1-phenyl-pyrrole-2,4-dicarboxylate

A mixture of diethyl3-(2-methoxyethyl)-5-methyl-1H-pyrrole-2,4-dicarboxylate (100 mg, 0.35mmol), phenyl boronic acid (130 mg, 1.06 mmol), copper acetate (130 mg,0.71 mmol), dry pyridine (110 mg, 1.40 mmol), molecular sieves (400 mg)and dichloromethane (10 mL) was purged with argon gas for 30 min andstirred overnight. The mixture was filtered through a celite bed, washedwith dichloromethane (15 mL) and concentrated under reduced pressure.The crude compound was purified by column chromatography over silica gel(100-200 mesh) using 20% ethyl acetate/pet ether as eluent to afforddiethyl 3-(2-methoxyethyl)-5-methyl-1-phenyl-pyrrole-2,4-dicarboxylate(50 mg, 40%) as a colourless oil.

Reference Example 102 Ethyl 3-cyclobutylprop-2-enoate

A mixture of cyclobutyl-methanol (8.00 g, 93.02 mmol),ethoxycarbonylmethylene triphenylphosphorane (19.42 g, 55.81 mmol) andpyridine (3 mL) were dissolved in dry chloroform (100 mL) and heated at70° C. Manganese dioxide (97.11 g, 1.12 mol) was added portion wise overa period of 5 h (with 1 h gap between each addition) and refluxing wascontinued for 20 h. The reaction mixture was cooled to room temperature,filtered over celite and washed with chloroform. The filtrate wasconcentrated and the residue subjected to column chromatography oversilica gel (60-120 mesh) using 0% to 15% of ethyl acetate in pet etheras eluent to afford ethyl 3-cyclobutylprop-2-enoate (2.10 g, 15%) as aliquid.

Reference Example 103 Ethyl 4-cyclobutyl-1H-pyrrole-3-carboxylate

Toluenesulfonylmethyl isocyanide (3.04 g, 15.59 mmol) was added to thestirred solution of ethyl 3-cyclobutylprop-2-enoate (2.00 g, 12.99 mmol)in a mixture of dimethylsulfoxide (2 mL) and diethyl ether (30 mL) andstirred for 45 min. The resulting mixture was added to a slurry ofsodium hydride (675 mg, 38.14 mmol, 60% in mineral oil) in diethyl ether(10 mL) over a period of 30 min then stirred for a further 1 h. Thereaction mixture was quenched with saturated ammonium chloride solution,the organics were separated and the aqueous layer was extracted withdiethyl ether (4×10 mL). The combined organic layer was washed withwater, brine, dried over anhydrous sodium sulphate, filtered andconcentrated. The residue was subjected to column chromatography oversilica gel (100-200 mesh) using 0% to 15% of ethyl acetate in pet-etheras eluent, concentrated and dried under reduced pressure to afford ethyl4-cyclobutyl-1H-pyrrole-3-carboxylate (1.70 g, 67%) as a liquid.

Reference Example 104 1,5-Dimethyl-3-phenyl-pyrrole-2,4-dicarboxylicacid

A solution of sodium hydroxide (101 g, 2.53 mol) in water (340 mL) wasadded to a solution of diethyl1,5-dimethyl-3-phenyl-pyrrole-2,4-dicarboxylate (80 g, 0.25 mol) inethanol (340 mL) and heated at reflux for 15 h. Ethanol was removedunder reduced pressure and the residue diluted with water (200 mL) andchilled to 0° C. Concentrated hydrochloric acid (˜150 mL) was slowlyadded to adjust pH to ˜2, while maintaining temperature below 10° C. andthe mixture was stirred for 30 min. The precipitated solid was filtered,washed with water (100 mL) and petroleum ether (200 mL) and dried undervacuum at 60° C. to afford1,5-dimethyl-3-phenyl-pyrrole-2,4-dicarboxylic acid (60 g, 91%) as awhite solid.

Reference Examples 105 to 145

The compounds set out below were prepared in a manner analogous toReference Example 104:

Reference Example Compound 1053-(2-Furyl)-1,5-dimethyl-pyrrole-2,4-dicarboxylic acid 1061,5-Dimethyl-3-(2-thienyl)pyrrole-2,4-dicarboxylic acid 1073-Isopropyl-1,5-dimethyl-pyrrole-2,4-dicarboxylic acid 1081,5-Dimethyl-3-tetrahydropyran-4-yl-pyrrole-2,4- dicarboxylic acid 1091,4-Dimethyl-3-phenyl-pyrrole-2-carboxylic acid 1105-Isopropyl-1-methyl-3-phenyl-pyrrole-2,4-dicarboxylic acid 1113-Isopropyl-1-(2-methoxyethyl)-5-methyl-pyrrole-2,4- dicarboxylic acid112 1-(2-Ethoxyethyl)-5-methyl-3-phenyl-pyrrole-2,4- dicarboxylic acid113 1-(3-Methoxypropyl)-5-methyl-3-phenyl-pyrrole-2,4- dicarboxylic acid114 1-Ethyl-5-methyl-3-phenyl-pyrrole-2,4-dicarboxylic acid 1155-Methyl-3-phenyl-1-propyl-pyrrole-2,4-dicarboxylic acid 1161-Butyl-5-methyl-3-phenyl-pyrrole-2,4-dicarboxylic acid 1171-Methyl-4-phenyl-pyrrole-2-carboxylic acid 1181-Benzyl-5-methyl-3-phenyl-pyrrole-2,4-dicarboxylic acid 1195-Methyl-3-phenyl-1H-pyrrole-2,4-dicarboxylic acid 1205-Ethyl-1-methyl-3-phenyl-pyrrole-2,4-dicarboxylic acid 1215-Ethyl-1-(2-methoxyethyl)-3-phenyl-pyrrole-2,4- dicarboxylic acid 1224-(2-Chlorophenyl)-1-(2-methoxyethyl)pyrrole-2-carboxylic acid 1234-Isobutyl-1-(2-methoxyethyl)pyrrole-3-carboxylic acid 1244-(3-Chlorophenyl)-1-(2-methoxyethyl)pyrrole-2-carboxylic acid 1255-Isopropyl-1-(2-methoxyethyl)-3-phenyl-pyrrole-2,4- dicarboxylic acid126 3-(2-Methoxyethyl)-5-methyl-1-phenyl-pyrrole-2,4- dicarboxylic acid127 4-Isopropyl-1H-pyrrole-3-carboxylic acid 1284-Isobutyl-1H-pyrrole-3-carboxylic acid 1295-methyl-3-phenyl-1-(2-pyridylmethyl)pyrrole-2,4- dicarboxylic acid 1305-Methyl-3-phenyl-1-(4-pyridylmethyl)pyrrole-2,4- dicarboxylic acid 1314-Cyclobutyl-1H-pyrrole-3-carboxylic acid 1321-Methyl-3-phenyl-5-propyl-pyrrole-2,4-dicarboxylic acid 1335-Ethyl-1-(methoxymethyl)-3-phenyl-pyrrole-2,4-dicarboxylic acid 1345-(2-methoxyethyl)-1-methyl-3-phenyl-pyrrole-2,4- dicarboxylic acid 1351-(Ethoxymethyl)-5-methyl-3-phenyl-pyrrole-2,4-dicarboxylic acid 1365-Methyl-1-(2-methylsulfanylethyl)-3-phenyl-pyrrole-2,4- dicarboxylicacid 137 1-(3-Hydroxypropyl)-5-methyl-3-phenyl-pyrrole-2,4- dicarboxylicacid 138 5-Methyl-1-(methylsulfanylmethyl)-3-phenyl-pyrrole-2,4-dicarboxylic acid 1391-(2-Methoxyethoxymethyl)-5-methyl-3-phenyl-pyrrole-2,4- dicarboxylicacid 140 5-Methyl-3-phenyl-1-(propoxymethyl)pyrrole-2,4-dicarboxylicacid 141 1-(2-Methoxyethyl)-5-methyl-3-phenyl-pyrrole-2,4- dicarboxylicacid 142 5-Methyl-1-(2-phenoxyethyl)-3-phenyl-pyrrole-2,4- dicarboxylicacid 143 1-(4-methoxybut-2-enyl)-5-methyl-3-phenyl-pyrrole-2,4-dicarboxylic acid 1445-Methyl-1-[(2-methyloxazol-4-yl)methyl]-3-phenyl-pyrrole-2,4-dicarboxylic acid 1451-(Butoxymethyl)-5-methyl-3-phenyl-pyrrole-2,4-dicarboxylic acid

Reference Example 146 4-Phenyl-1H-pyrrole-2-carboxylic acid

A mixture of ethyl 4-phenyl-1H-pyrrole-2-carboxylate (700 mg, 3.25mmol), aqueous sodium hydroxide (10% w/v, 10 mL) and ethanol (10 mL)were stirred at room temperature over night. The ethanol was evaporatedin vacuo, then water (20 mL) was added and the organics were extractedwith ethyl acetate (3×20 mL). The aqueous layer was acidified with 2NHCl (to pH 3) and extracted with ethyl acetate (3×20 mL). The combinedorganic layer was washed with water, brine (20 mL), dried over anhydroussodium sulphate and concentrated under reduced pressure to afford4-phenyl-1H-pyrrole-2-carboxylic acid (400 mg, 66%) as a solid.

Reference Examples 147 to 150

The compounds set out below were prepared in a manner analogous toReference Example 146:

Reference Example Compound 1471-(2-Methoxyethyl)-4-phenyl-pyrrole-2-carboxylic acid 1481-(Methoxymethyl)-4-phenyl-pyrrole-2-carboxylic acid 1494-(2-Thienyl)-1H-pyrrole-3-carboxylic acid 1504-(3-Thienyl)-1H-pyrrole-3-carboxylic acid

Reference Example 151 & 152 Dimethyl1-(3-methoxypropyl)-5-methyl-3-phenyl-pyrrole-2,4-dicarboxylate (151) &4-methoxycarbonyl-1-(3-methoxypropyl)-5-methyl-3-phenyl-pyrrole-2-carboxylicacid (152)

Sodium methoxide (190 mg, 3.50 mmol) was added to a solution of diethyl1-(3-chloropropyl)-5-methyl-3-phenyl-pyrrole-2,4-dicarboxylate (1.1 g,2.91 mmol) in methanol (10 mL) and stirred at reflux for 28 h. Thereaction mixture was cooled to room temperature and concentrated todryness. The residue was dissolved in water and the aqueous layer wasextracted with dichloromethane. The organic layer was washed with water,brine, dried over anhydrous sodium sulphate and concentrated in vacuo toafford dimethyl1-(3-methoxypropyl)-5-methyl-3-phenyl-pyrrole-2,4-dicarboxylate (330 mg,33%) as a yellow oil. The aqueous layer was acidified with 2Nhydrochloric acid to pH 2 and extracted with ethyl acetate. The combinedorganic layer was washed with water, brine, dried over anhydrous sodiumsulphate and concentrated to afford4-methoxycarbonyl-1-(3-methoxypropyl)-5-methyl-3-phenyl-pyrrole-2-carboxylicacid (170 mg, 18%) as a pink oil.

Reference Example 153

The compound set out below was prepared in a manner analogous toReference Example 151 & 152:

Reference Example Compound 153 Diethyl1-(4-methoxybut-2-enyl)-5-methyl-3-phenyl-pyrrole- 2,4-dicarboxylate

Reference Example 154 Ethyl4-bromo-5-methyl-3-phenyl-1H-pyrrole-2-carboxylate

N-Bromo succinimide (1.40 g, 7.87 mmol) was added to a solution of ethyl5-methyl-3-phenyl-1H-pyrrole-2-carboxylate (1.5 g, 6.55 mmol) in amixture of dioxane (10 mL) and acetic acid (20 mL) at 0° C. The reactionmixture was stirred at 0° C. for 15 min. The reaction mixture was warmedto room temperature and stirred for another 15 min. The mixture wasquenched with 2N NaOH solution and the organic layer was separated,washed with water, brine solution, dried over anhydrous sodium sulfateand concentrated under reduced pressure to give ethyl4-bromo-5-methyl-3-phenyl-1H-pyrrole-2-carboxylate (1.68 g, 84%) as asolid.

Reference Example 155 Ethyl4-bromo-1,5-dimethyl-3-phenyl-pyrrole-2-carboxylate

60% Sodium hydride (320 mg, 8.03 mmol) in mineral oil was added to asolution of 4-bromo-5-methyl-3-phenyl-1H-pyrrole-2-carboxylate (1.65 g,5.36 mmol) in tetrahydrofuran (20 mL) at 0° C. The reaction mixture wasstirred at 0° C. for 15 min and then the methyl iodide (0.66 mL, 10.72mmol) was added at 0° C. and then the reaction mixture was allowed towarm to room temperature overnight. The reaction mixture was quenchedwith ice and the solvent was evaporated. The organics were extractedwith ethyl acetate and the organic layer was washed with water, brineand dried over anhydrous sodium sulfate. The ethyl acetate layer wasconcentrated under reduced pressure to afford ethyl4-bromo-1,5-dimethyl-3-phenyl-pyrrole-2-carboxylate (1.68 g, 98%) as aliquid.

Reference Example 156 4-Bromo-1,5-dimethyl-3-phenyl-pyrrole-2-carboxylicacid

A solution of potassium hydroxide (1.40 g, 25.0 mmol) in water (3 mL)was added to a solution of ethyl4-bromo-1,5-dimethyl-3-phenyl-pyrrole-2-carboxylate (1.60 g, 4.97 mmol)in ethanol (5 mL) and the reaction mixture was refluxed overnight. Thesolvent was evaporated and the residue was washed with diethyl ether.The resultant filter cake was acidified with diluted HCl and extractedwith ether. The organic layer was washed with water, brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure to give4-bromo-1,5-dimethyl-3-phenyl-pyrrole-2-carboxylic acid (1.0 g, 69%) asa solid.

Reference Examples 157

The compound set out below was prepared in a manner analogous toReference Example 156:

Reference Example Compound 1574-Bromo-5-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid

Reference Example 158 1,2-Dimethyl-4-phenyl-pyrrole

A suspension of 1,5-dimethyl-3-phenyl-pyrrole-2,4-dicarboxylic acid (60g, 0.23 mol) and 2-aminoethanol (300 mL) was heated to 175° C. under anitrogen atmosphere for 30 min. The mixture was allowed to cool to roomtemperature, diluted with water (100 mL) and extracted with ethylacetate (2×100 mL). The combined organic layers were washed successivelywith water (3×100 mL) and brine (2×100 mL), dried over anhydrous sodiumsulfate and concentrated in vacuo at a temperature below 40° C. toafford the crude product. Flash column chromatography over neutralalumina using 5% ethyl acetate in petroleum ether as eluent afforded1,2-dimethyl-4-phenyl-pyrrole (30.5 g, 78%) as a white solid.

Reference Examples 159 to 207

The compounds set out below were prepared in a manner analogous toReference Example 158:

Reference Example Compound 159 4-(2-Furyl)-1,2-dimethyl-pyrrole 1601,2-Dimethyl-4-(2-thienyl)pyrrole 161 4-Isopropyl-1,2-dimethyl-pyrrole162 1,2-Dimethyl-4-tetrahydropyran-4-yl-pyrrole 1631,3-Dimethyl-4-phenyl-pyrrole 164 2-Isopropyl-1-methyl-4-phenyl-pyrrole165 4-Isopropyl-1-(2-methoxyethyl)-2-methyl-pyrrole 1661-(2-Ethoxyethyl)-2-methyl-4-phenyl-pyrrole 1671-(3-Methoxypropyl)-2-methyl-4-phenyl-pyrrole 1681-Ethyl-2-methyl-4-phenyl-pyrrole 169 2-Methyl-4-phenyl-1-propyl-pyrrole170 1-Butyl-2-methyl-4-phenyl-pyrrole 171 3-Phenyl-1H-pyrrole 1721-Methyl-3-phenyl-pyrrole 173 1-(2-Methoxyethyl)-3-phenyl-pyrrole 1741-Benzyl-2-methyl-4-phenyl-pyrrole 175 2-Methyl-4-phenyl-1H-pyrrole 1762-Ethyl-1-methyl-4-phenyl-pyrrole 1772-Ethyl-1-(2-methoxyethyl)-4-phenyl-pyrrole 1783-(2-Chlorophenyl)-1-(2-methoxyethyl)pyrrole 1793-(4-Chlorophenyl)-1-(2-methoxyethyl)pyrrole 1801-(Methoxymethyl)-3-phenyl-pyrrole 181 3-(2-Thienyl)-1H-pyrrole 1823-Isobutyl-1-(2-methoxyethyl)pyrrole 1833-(3-Chlorophenyl)-1-(2-methoxyethyl)pyrrole 1843-(3-Thienyl)-1H-pyrrole 1852-Isopropyl-1-(2-methoxyethyl)-4-phenyl-pyrrole 1864-(2-Methoxyethyl)-2-methyl-1-phenyl-pyrrole 187 3-Isopropyl-1H-pyrrole188 3-Isobutyl-1H-pyrrole 189 3-Bromo-1,2-dimethyl-4-phenyl-pyrrole 1902-[(2-Methyl-4-phenyl-pyrrol-1-yl)methyl]pyridine 1913-Bromo-2-methyl-4-phenyl-1H-pyrrole 1924-[(2-Methyl-4-phenyl-pyrrol-1-yl)methyl]pyridine 1933-Cyclobutyl-1H-pyrrole 194 1-Methyl-4-phenyl-2-propyl-pyrrole 1952-Ethyl-1-(methoxymethyl)-4-phenyl-pyrrole 1962-(2-Methoxyethyl)-1-methyl-4-phenyl-pyrrole 1971-(Ethoxymethyl)-2-methyl-4-phenyl-pyrrole 1982-Methyl-1-(2-methylsulfanylethyl)-4-phenyl-pyrrole 1993-(2-Methyl-4-phenyl-pyrrol-1-yl)-propan-1-ol 2002-Methyl-1-(methylsulfanylmethyl)-4-phenyl-pyrrole 2011-(2-Methoxyethoxymethyl)-2-Methyl)-4-phenyl-pyrrole 2022-Methyl-4-phenyl-1-(propoxymethyl)pyrrole 2031-(2-Methoxyethyl)-2-methyl-4-phenyl-pyrrole 2042-Methyl-1-(2-phenoxyethyl)-4-phenyl-pyrrole 2051-(4-Methoxybut-2-enyl)-2-methyl-4-phenyl-pyrrole 2062-Methyl-4-[(2-methyl-4-phenyl-pyrrol-1-yl)methyl]oxazole 2071-(Butoxymethyl)-2-methyl-4-phenyl-pyrrole

Reference Examples 208 and 2092-Phenyl-5,6,7,8-tetrahydropyrrolo[1,2-a]azepin-9-one (208) &1-Phenyl-5,6,7,8-tetrahydropyrrolo[1,2-a]azepin-9-one (209)

Dry hydrogen chloride gas was bubbled into a stirred solution of5-(3-phenyl-pyrrol-1-yl)pentanenitrile (1.45 g, 6.47 mmol) in drydiethyl ether (50 mL) and boron trifluoride etherate (2 mL) at −5 to 0°C. When the mixture became saturated with the hydrogen chloride gas, itwas allowed to stand for 24 h. Excess diethyl ether was removed in vacuoand the residue hydrolyzed by adding dilute ammonium hydroxide (20 mL)and chloroform (30 mL). The reaction mixture was refluxed for 12 h andthe chloroform layer separated. The chloroform layer was dried overanhydrous sodium sulphate and concentrated under reduced pressure toafford a mixture of2-phenyl-5,6,7,8-tetrahydro-pyrrolo[1,2-a]azepin-9-one &1-phenyl-5,6,7,8-tetrahydro-pyrrolo[1,2-a]azepin-9-one (1.50 g, 99%) asa gummy solid.

Reference Example 210 and 2112-Phenyl-6,7,8,9-tetrahydro-5H-pyrrololo[1,2-a]azepine (210) &1-phenyl-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine (211)

80% Hydrazine hydrate (0.56 mL, 9.0 mmol) was added in one portion to astirred solution of2-phenyl-5,6,7,8-tetrahydro-pyrrolo[1,2-a]azepin-9-one &1-phenyl-5,6,7,8-tetrahydro-pyrrolo[1,2-a]azepin-9-one (50 mg, 2.22mmol) and potassium hydroxide (500 mg, 8.90 mmol) in diethylene glycol(6 mL) and heated at 160-165° C. for 16 h. The reaction mixture wascooled, poured into ice-water (20 mL) and extracted with diethyl ether(3×20 mL). The combined organic layer was washed with brine (20 mL),dried over anhydrous sodium sulphate, concentrated under reducedpressure to give the crude compound which was purified by columnchromatography over neutral alumina using 20% ethyl acetate in petroleumether as eluent to afford a mixture of2-phenyl-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine &1-phenyl-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine (170 mg, 36%) as anoil.

Reference Example 212(3-Dimethylamino-2-phenyl-prop-2-enylidene)-dimethyl-ammoniumperchlorate

Phosphorus oxychloride (6.8 g, 44.4 mmol) was added to anhydrousdimethylformamide (16 g, 220 mmol) over a period of 15 min at 0-5° C.,then warmed to room temperature and stirred for 1 h. Phenylacetic acid(2.0 g, 14.7 mmol) was added and the reaction mixture stirred at 90-100°C. for 16 h. The reaction mixture was quenched by pouring into ice waterwith vigorous stirring. A solution of 70% perchloric acid (1.88 mL, 2.2g, 22.0 mmol) in water (5 mL) was added drop-wise with vigorousstirring. A solid precipitated which was filtered, washed with ice coldwater and dried in vacuo to afford(3-dimethylamino-2-phenyl-prop-2-enylidene)-dimethyl-ammoniumperchlorate (2.0 g, 66%) as a brown solid.

Reference Examples 213 to 215

The compounds set out below were prepared in a manner analogous toReference Example 212:

Reference Example Compound 213[2-(2-Chlorophenyl)-3-dimethylamino-prop-2- enylidene]-dimethyl-ammoniumperchlorate 214 [2-(4-Chlorophenyl)-3-dimethylamino-prop-2-enylidene]-dimethyl-ammonium perchlorate 215[2-(3-Chlorophenyl)-3-dimethylamino-prop-2-enylidene]-dimethyl-ammonium; oxalate

Reference Example 216 Ethyl 4-phenyl-1H-pyrrole-2-carboxylate

Sodium metal (900 mg, 41.0 mmol) was added to dry ethanol (150 mL) andallowed to dissolve over 30 min. Glycine methyl ester hydrochloride (3.2g, 25.0 mmol) and(3-dimethylamino-2-phenyl-prop-2-enylidene)-dimethyl-ammoniumperchlorate (5.0 g, 16.0 mmol) were added successively and the reactionmixture heated at reflux for 16 h. Ethanol was evaporated in vacuo, theresidue diluted with water and extracted with chloroform. The organiclayer was washed with water, brine, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The crude product obtained waspurified by column chromatography over neutral alumina using 10% ethylacetate in petroleum ether as eluent to afford ethyl4-phenyl-1H-pyrrole-2-carboxylate (2.0 g, 57%) as a solid.

Reference Examples 217 to 219

The compounds set out below were prepared in a manner analogous toReference Example 219:

Reference Example Compound 217 Ethyl4-(2-chlorophenyl)-1H-pyrrole-2-carboxylate 218 Ethyl4-(4-chlorophenyl)-1H-pyrrole-2-carboxylate 219 Ethyl4-(3-chlorophenyl)-1H-pyrrole-2-carboxylate

Reference Example 220 Ethyl1-(3-ethoxy-3-oxo-propyl)-4-phenyl-pyrrole-2-carboxylate

Potassium tert-butoxide (100 mg, 0.90 mmol), ethyl4-phenyl-1H-pyrrole-2-carboxylate (1.0 g, 4.65 mmol) and ethyl acrylate(50 mL) were heated at reflux for 90 min. The reaction mixture wasallowed to cool to room temperature and neutralized with acetic acid (1mL). Excess ethyl acrylate was evaporated in vacuo, the residue dilutedwith water and extracted with chloroform. The organic layer was driedover anhydrous sodium sulfate, filtered and concentrated in vacuo togive the crude compound. Purification by column chromatography overneutral alumina using 5% ethyl acetate in petroleum ether as eluent gaveethyl 1-(3-ethoxy-3-oxo-propyl)-4-phenyl-pyrrole-2-carboxylate (1.0 g,69%) as an oil.

Reference Example 221 Diethyl1-(ethoxymethyl)-5-methyl-3-phenyl-pyrrole-2,4-dicarboxylate

Potassium tert-butoxide (557 mg, 4.97 mmol) was added to a stirredsolution of diethyl 5-methyl-3-phenyl-1H-pyrrole-2,4-dicarboxylate (600mg, 1.99 mmol) in dimethylsulfoxide (15 mL) at 10° C. and stirred atambient temperature for 1 h. Upon cooling to 10° C., chloromethyl ethylether (377 mg, 3.99 mmol) was added and stirred at ambient temperaturefor 12 h. The mixture was poured onto ice-water and extracted withdiethyl ether (5×10 mL). The combined organic layers were washed withwater, brine, dried over anhydrous sodium sulphate and filtered. Thefiltrate was concentrated in vacuo and subjected to columnchromatography over silica gel (100-200 mesh) using 8% ethyl acetate inpetroleum ether as eluent to afford diethyl1-(ethoxymethyl)-5-methyl-3-phenyl-pyrrole-2,4-dicarboxylate (400 mg,56%) as a liquid.

Reference Examples 222 to 227

The compounds set out below were prepared in a manner analogous toReference Example 221:

Reference Example Compound 222 Diethyl1-(2-methoxyethoxymethyl)-5-methyl-3-phenyl- pyrrole-2,4-dicarboxylate223 Diethyl 5-methyl-3-phenyl-1-(propoxymethyl)pyrrole-2,4-dicarboxylate 224 Diethyl1-(4-chlorobut-2-enyl)-5-methyl-3-phenyl-pyrrole- 2,4-dicarboxylate 2251-(4-Methoxybutyl)-2-methyl-4-phenyl-pyrrole 226 Diethyl5-methyl-1-[(2-methyloxazol-4-yl)methyl]-3-phenyl-1H-pyrrole-2,4-dicarboxylate 227 Diethyl1-(butoxymethyl)-5-methyl-3-phenyl-pyrrole-2,4- dicarboxylate

Reference Example 228 Diethyl1-(3-hydroxypropyl)-5-methyl-3-phenyl-pyrrole-2,4-dicarboxylate

Potassium tert-butoxide (744 mg, 6.64 mmol) was added to a stirredsolution of diethyl 5-methyl-3-phenyl-1H-pyrrole-2,4 dicarboxylate (1.00g, 1.99 mmol) in dimethylsulfoxide (15 mL) at 10° C. and stirred atambient temperature for 1 h. The mixture was cooled to 10° C.,3-bromo-1-propanol (738 mg, 5.31 mmol) added and stirring continued atambient temperature for 12 h. The mixture was poured onto ice-water andextracted with diethyl ether (5×10 mL). The combined organic layers werewashed with water, brine, dried over anhydrous sodium sulphate andfiltered. The filtrate was concentrated in vacuo and subjected to columnchromatography over silica gel (100-200 mesh) using 40% of ethyl acetatein petroleum ether as eluent to afford of diethyl1-(3-hydroxypropyl)-5-methyl-3-phenyl-pyrrole-2,4-dicarboxylate (600 mg,50%) as a liquid.

Reference Example 229 1-(2-Carboxyethyl)-4-phenyl-pyrrole-2-carboxylicacid

10% Aqueous sodium hydroxide solution (20 mL) was added to a stirredsolution of ethyl1-(3-ethoxy-3-oxo-propyl)-4-phenyl-pyrrole-2-carboxylate (2.0 g, 6.35mmol) in ethanol (20 mL). The reaction mixture was stirred for 2 h at50-60° C. The ethanol was evaporated in vacuo and then water added tothe residue and acidified with 5N HCl to pH 4-5. The precipitated solidwas filtered, washed with water and dried in vacuo to afford1-(2-carboxyethyl)-4-phenyl-pyrrole-2-carboxylic acid (900 mg, 56%) as asolid.

Reference Example 230 6-Phenyl-2,3-dihydropyrrolizin-1-one

Anhydrous sodium acetate (200 mg, 2.5 mmol) was added to a stirredsolution of 1-(2-carboxyethyl)-4-phenyl-pyrrole-2-carboxylic acid (1.0g, 3.90 mmol) in acetic anhydride (10 mL) and heated at reflux for 16 h.Excess acetic anhydride was evaporated in vacuo and water was added. Themixture was extracted with ethyl acetate and the separated organic layerwas washed with water, brine, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to afford the crude product.Purification by column chromatography over neutral alumina using 25%ethyl acetate in petroleum ether as eluent afforded6-phenyl-2,3-dihydropyrrolizin-1-one (200 mg, 27%) as a brown solid.

Reference Example 231 (4-Phenyl-M-pyrrol-2-yl)methanol

A solution of ethyl 4-phenyl-1H-pyrrole-2-carboxylate (1 g, 5.58 mmol)in tetrahydrofuran (10 mL) was added to a suspension of lithium aluminumhydride (300 mg, 8.10 mmol) in tetrahydrofuran (20 mL) at 0° C. Thereaction mixture was slowly warmed to ambient temperature and stirredfor 5 h. The mixture was slowly added to saturated sodium sulphatefollowed by extraction with ethyl acetate (2×25 mL). The combinedorganic layers were washed with water, brine, dried over anhydroussodium sulfate and concentrated in vacuo to afford(4-phenyl-1H-pyrrol-2-yl)methanol (800 mg, 84%) as a solid.

Reference Example 232 2-Methyl-1H-pyrrole

Lithium aluminium hydride (899 mg, 23.6 mmol) was added to the solutionof 1H-pyrrole-2-carbaldehyde (750 mg, 7.9 mmol) in tetrahydrofuran (10mL) at 0° C. then the mixture was heated at reflux for 16 h. The mixturewas quenched into ice water and extracted with ethyl acetate. Thecombined organic phases were washed with water, brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to obtain a residue which was purified by washing withn-pentane. Drying afforded 2-methyl-1H-pyrrole (500 mg, 77%).

Reference Example 233 4-Iodo-1H-pyrrole-2-carbaldehyde

A solution of 1H-pyrrole-2-carbaldehyde (7.0 g, 73.6 mmol) intetrahydrofuran (45 mL) was cooled to −75° C. N-iodosuccinimide (19.8 g,88.3 mmol) was added portionwise over 20 min and the reaction mixturewas then stirred for 2 h at −75° C. Water and petroleum ether were addedand the reaction mixture warmed to ambient temperature. The organiclayer was separated and the aqueous phase extracted with petroleumether. The combined organic layers were washed with water, brine, driedover anhydrous sodium sulfate, filtered and concentrated in vacuo toafford 4-iodo-1H-pyrrole-2-carbaldehyde (13.2 g, 81%) as a black solid.

Reference Example 234 Chloro(methoxy)methane

Dry HCl gas was passed through a suspension of paraformaldehyde (30.0 g,1 mol) in methanol (32.0 g, 1 mol) at 0-5° C. for 6 h. The reactionmixture was filtered and the organic layer in the filtrate was separatedand dried over anhydrous calcium chloride for 16 h. The organic layerwas distilled using a Vigreux column to afford chloro(methoxy)methane(20 g, 25%) of 90% purity (by Gas Chromatography).

Reference Example 235 Isopropyl 2-chloroacetate

Chloro acetyl chloride (5 g, 0.045 mmol) was added drop wise toisopropanol (2.7 g, 0.045 mmol) at 0° C. The mixture was heated to 80°C. under a nitrogen atmosphere and maintained at this temperature for 3h. The compound was purified by fractional distillation in vacuo toafford isopropyl 2-chloroacetate (5 g, 84%) as a liquid.

Reference Example 236 Ethyl 2-(2-formyl-4-iodo-pyrrol-1-yl)acetate

Sodium hydride (1.62 g, 60% w/w dispersion in mineral oil, 67.9 mmol)was added to a solution of 4-iodo-1H-pyrrole-2-carbaldehyde (5.0 g, 22.6mmol) in tetrahydrofuran (30 mL) over 10 min. The reaction mixture wasstirred for 15 min, then ethyl bromoacetate (7.56 g, 45.2 mmol) wasadded and the mixture stirred for 2 h at ambient temperature. Thereaction was quenched with methanol and concentrated in vacuo. The crudecompound was then extracted into ethyl acetate. The organic layer washedwith water, brine, dried over anhydrous sodium sulfate, filtered andconcentrated under in vacuo to afford the crude compound. Purificationby column chromatography over silica gel (100-200 mesh) using 2% ethylacetate in petroleum ether afforded ethyl2-(2-formyl-4-iodo-pyrrol-1-yl)acetate (3.4 g, 49%).

Reference Examples 237 to 240

The compounds set out below were prepared in a manner analogous toReference Example 236:

Reference Example Compound 2371-(Methoxymethyl)-2-methyl-4-phenyl-pyrrole 238 Methyl1-(methoxymethyl)-4-phenyl-pyrrole-2-carboxylate 239 Isopropyl2-(2-methyl-4-phenyl-pyrrol-1-yl)acetate 240 tert-Butyl2-(3-isopropylpyrrol-1-yl)acetate

Reference Example 241 Ethyl 2-(2-formyl-4-phenyl-pyrrol-1-yl)acetate

A solution of ethyl 2-(2-formyl-4-iodo-pyrrol-1-yl)acetate (3.0 g, 9.77mmol) in dimethylformamide (25 mL) was purged with argon gas for 10 min.Bis-(triphenylphosphine)-palladium(II) chloride (0.48 g, 0.68 mmol) wasadded and the mixture was purged with argon gas for 5 min. Anhydrouspotassium phosphate (6.18 g, 29.3 mmol) and phenylboronic acid (1.43 g,11.7 mmol) were added successively and the reaction mixture purged withargon gas for 10 min, then heated to 110° C. and maintained at thattemperature for 4 h. The resulting mixture was allowed to cool toambient temperature and diethyl ether added. The reaction mixture wasfiltered, the filtrate being washed with water and the separated aqueousphase being further extracted with diethyl ether. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to afford the crude product.Purification by column chromatography over silica gel (100-200 mesh)using 8% ethyl acetate in petroleum ether as eluent afforded ethyl2-(2-formyl-4-phenyl-pyrrol-1-yl)acetate (680 mg, 27%).

Reference Example 2422-Methyl-7-phenyl-1,2-dihydropyrrolo[1,2-a]pyrazin-3-one

Acetic acid was added to a solution of methylamine (0.45 mL, 5.30 mmol,40% in water) in tetrahydrofuran (8 mL) to adjust the pH to 6. Asolution of (2-formyl-4-phenyl-pyrrol-1-yl)-acetic acid ethyl ester (680mg, 2.65 mmol) in tetrahydrofuran (4 mL) was added and the reactionmixture stirred at ambient temperature for 45 min. Sodiumcyanoborohydride (0.33 g, 5.30 mmol) was added and the reaction mixtureheated at 75 C for 18 h. Concentration in vacuo yielded a residue whichwas partitioned between water and ethyl acetate. The organic layer waswashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to afford the crude product. Purification bycolumn chromatography over silica gel (100-200 mesh) using 30% ethylacetate in petroleum ether afforded2-methyl-7-phenyl-1,2-dihydropyrrolo[1,2-a]pyrazin-3-one (180 mg, 30%)as a solid.

Reference Example 2432-methyl-7-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine

Borane-dimethyl sulfide complex (0.25 mL, 2.6 mmol) was added to coldtetrahydrofuran (6 mL) and stirred for 10 min.2-Methyl-7-phenyl-1,2-dihydropyrrolo[1,2-a]pyrazin-3-one (180 mg, 0.8mmol) was added, and the reaction mixture allowed to warm to roomtemperature and stirred for 3 h. The mixture was poured slowly intosaturated ammonium chloride solution and extracted with ethyl acetate.The organic layer was washed with water then brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give the crudecompound. Purification by column chromatography over silica gel (100-200mesh) using 8% ethyl acetate in petroleum ether afforded2-methyl-7-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine (110 mg, 64%) asa solid.

Reference Example 244 4-Iodo-1-isopropyl-pyrrole-2-carbaldehyde

Sodium hydride (860 mg, 55% in mineral oil, 19.7 mmol) was added to asolution of 4-iodo-pyrrole-2-carbaldehyde (3.0 g, 13.2 mmol) in drydimethylformamide at ambient temperature under a nitrogen atmosphere.After stirring for 15 min 2-bromopropane (3.87 mL, 40.9 mmol) was addedand the reaction mixture heated at reflux for 16 h. The mixture wasallowed to cool to ambient temperature, quenched with water andextracted with diethyl ether. The combined organic layers were washedwith water, brine, dried over anhydrous sodium sulfate and concentratedin vacuo to give a crude residue. Purification by column chromatographyover silica gel (60-120 mesh) using 2% ethyl acetate in petroleum etherafforded 4-iodo-1-isopropyl-pyrrole-2-carbaldehyde (1.5 g, 43%) as abrown liquid.

Reference Example 245

The compound set out below was prepared in a manner analogous toReference Example 245.

Reference Example Compound 2454-Iodo-1-(2-methoxyethyl-pyrrole-2-carbaldehyde

Reference Example 246 1-(2-Hydroxyethyl)-4-iodo-pyrrole-2-carbaldehyde

Potassium hydroxide (3.1 g, 54.3 mmol) was added to a stirred solutionof 4-iodo-1H-pyrrole-2-carbaldehyde (4.0 g, 18.1 mmol) in dioxane (20mL). 2-Bromo-ethanol (2.56 mL, 36.2 mmol) was added to the reactionmixture and heated at 60° C. for 16 h. The reaction mixture was cooledto room temperature and the pH was adjusted to ˜6 by the addition ofacetic acid. The reaction mixture was then concentrated in vacuo to givea residue which was partitioned between water and ethyl acetate. Theorganic phase was washed with water, brine, dried over anhydrous sodiumsulfate and concentrated in vacuo to give a residue which was purifiedby column chromatography over silica gel (100-200 mesh) using 10% ethylacetate in petroleum ether as eluent to afford1-(2-hydroxyethyl)-4-iodo-pyrrole-2-carbaldehyde (2.4 g, 50%) as acolourless solid.

Reference Example 247 2-(2-Formyl-4-iodo-pyrrol-1-yl)ethyl4-methylbenzenesulfonate

Triethylamine (3.3 mL, 23.8 mmol) was added to a stirred solution of1-(2-hydroxyethyl)-4-iodo-pyrrole-2-carbaldehyde (2.1 g, 7.92 mmol) indichloromethane (15 mL). The reaction mixture was chilled to 0° C. and4-methyl-benzenesulfonyl chloride (1.82 g, 9.51 mmol) was added over 15min. The reaction mixture was allowed to warm to ambient temperature andstirred overnight. Water was added, the organic phase separated and theaqueous phase extracted with dichloromethane. The combined organiclayers were washed with saturated sodium bicarbonate solution, brine,dried over anhydrous sodium sulfate and concentrated in vacuo to give aresidue which was purified by washing with petroleum ether to afford2-(2-formyl-4-iodo-pyrrol-1-yl)ethyl 4-methylbenzenesulfonate (2.4 g,72%) as a grey solid.

Reference Example 248 2-[2-(Hydroxymethyl)-4-iodo-pyrrol-1-yl]ethyl4-methylbenzenesulfonate

2-(2-Formyl-4-iodo-pyrrol-1-yl)ethyl 4-methylbenzenesulfonate (2.1 g,5.01 mmol) in ethanol (25 mL) was cooled to 0° C. and sodium borohydride(95 mg, 2.50 mmol) was added. After 30 min, the reaction mixture wasallowed to warm to ambient temperature and stirred for a further 1 h,after which time acetic acid was added and the mixture was concentratedin vacuo. The residue was partitioned between water and dichloromethaneand the organic phase was washed with water, brine, dried over anhydroussodium sulfate and concentrated in vacuo to give2-[2-(hydroxymethyl)-4-iodo-pyrrol-1-yl]ethyl 4-methylbenzenesulfonate(2.0 g, 95%) as a brownish crystalline solid.

Reference Example 249 7-Iodo-3,4-dihydro-4H-pyrrolo[2,1-c][1,4]oxazine

A solution of 2-[2-(hydroxymethyl)-4-iodo-pyrrol-1-yl]ethyl4-methylbenzenesulfonate (2.0 g, 4.79 mmol) in tetrahydrofuran (15 mL)was slowly added to a suspension of sodium hydride (120 mg, 60%dispersion in mineral oil; 4.75 mmol) in tetrahydrofuran (5 mL) andstirred at room temperature for 36 h. The reaction was quenched withwater and extracted with diethyl ether. The combined organic phases werewashed with water, brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to give a residue which was purifiedby column chromatography over silica gel using 2% ethyl acetate inpetroleum ether to afford7-iodo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine (800 mg, 66%) as acolorless crystalline solid.

Reference Example 250 7-Phenyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine

A solution of 7-iodo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine (800 mg,3.21 mmol) in dimethylformamide (8 mL) was purged with argon gas for 5min. Caesium carbonate (3.14 g, 9.64 mmol) and phenylboronic acid (590mg, 4.82 mmol) were added and the vessel was again purged with argon gasfor 5 min. Tetrakis(triphenylphosphine)palladium(0) (185 mg, 0.16 mmol)was added, the vessel was purged for a final time with argon gas for 5min and then the mixture was heated at 75° C. for 3 h. The reactionmixture was allowed to cool to ambient temperature, filtered and thenwater was added and mixture extracted with diethyl ether. The organicphase was washed with water, brine, dried over anhydrous sodium sulfateand concentrated in vacuo. The crude compound was purified by columnchromatography over silica gel (100-200 mesh) using 4% ethyl acetate inpetroleum ether to afford7-phenyl-3,4-dihydro-1H-pyrrolo[2,1-e][1,4]oxazine (90 mg, 14%) as apale yellow solid.

Reference Examples 251 and 252

The compounds set out below were prepared in a manner analogous toReference Example 250:

Reference Example Compound 2511-Isopropyl-4-phenyl-1H-pyrrole-2-carbaldehyde 2521-(2-Methoxyethyl)-4-phenyl-pyrrole-2-carbaldehyde

Reference Example 253 1-Phenylpyrrole-2-carbaldehyde

Phosphorus oxychloride (0.7 mL, 7.68 mmol) was added slowly to ice-colddimethylformamide (0.6 mL, 7.68 mmol). The mixture was warmed to roomtemperature and stirred for 15 min. A solution of 1-phenylpyrrole (1.0g, 6.98 mmol) in ethylene dichloride (5 mL) was added and the reactionmixture heated at reflux for 1 h. The mixture was cooled to 10° C. andquenched into 10% sodium acetate solution (20 mL). The organic layer wasseparated and the aqueous phase was extracted with ether. The combinedorganic layers were washed with water, brine, dried over anhydroussodium sulfate, filtered and concentrated under in vacuo to give a cruderesidue. Purification by column chromatography over silica gel (60-120mesh) using 2% ethyl acetate in petroleum ether as eluent gave1-phenylpyrrole-2-carbaldehyde (700 mg, 59%) as a colourless oil.

Reference Example 254 2-Methyl-1-phenyl-pyrrole

A mixture of 1-phenylpyrrole-2-carbaldehyde (700 mg, 4.1 mmol),potassium hydroxide (490 mg, 12.3 mmol) and hydrazine hydrate (0.8 mL,12.3 mmol) in ethylene glycol (15 mL) was stirred at ambient temperaturefor 30 min and then slowly heated to 150° C. and maintained for 2 h. Thereaction mixture was allowed to cool to ambient temperature, poured intoice-water and extracted with diethyl ether. The organic layer was washedwith water, brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give the crude compound. Purification by columnchromatography over silica gel (60-120 mesh) using petroleum ether aseluent to afford 2-methyl-1-phenyl-pyrrole (430 mg, 66%) as a yellowoil.

Reference Examples 255 to 256

The compounds set out below were prepared in a manner analogous toReference Example 254.

Reference Example Compound 255 6-Phenyl-2,3-dihydro-1H-pyrrolizine 2561-Isopropyl-2-methyl-4-phenyl-pyrrole

Reference Example 257 Ethyl 2-methyl-4-phenyl-pyrrole-1-carboxylate

n-Butyllithium (0.87 mL, 1.6M solution, 1.40 mmol) was added to a cold(below 0° C.) solution of 2-methyl-4-phenyl-1H-pyrrole (200 mg, 1.27mmol) in tetrahydrofuran (6 mL) and stirred at below 0° C. for 20 min.Ethyl chloroformate (0.1 mL, 1.02 mmol) was added slowly to the reactionmixture and stirred at 0 to 10° C. for 90 min. The reaction mixture wasquenched into saturated ammonium chloride solution and the aqueous layerwas extracted with ethyl acetate. The organic layer was washed withsaturated sodium bicarbonate solution, brine, dried over anhydroussodium sulphate and concentrated in vacuo to afford ethyl2-methyl-4-phenyl-pyrrole-1-carboxylate (250 mg, 86%) as a brown solid.

Reference Examples 258

The compound set out below was prepared in a manner analogous toReference Example 257.

Reference Example Compound 258 Methyl2-methyl-4-phenyl-pyrrole-1-carboxylate

Reference Example 259 3-Fluoro-1,2-dimethyl-4-phenyl-pyrrole

n-Butyllithium (2.06 mL, 1.6M solution, 3.30 mmol) was added to asolution of 3-bromo-1,2-dimethyl-4-phenyl-pyrrole (550 mg, 2.20 mmol) intetrahydrofuran (10 mL) at −78° C. and the reaction mixture was stirredat −78° C. for 30 min. A solution of n-fluorodibenzene sulfonamide (901mg, 2.86 mmol) in tetrahydrofuran (8 mL) was added to the reactionmixture at −78° C. and the reaction mixture was stirred at thistemperature for another 1 h. The reaction mixture was allowed to warm toambient temperature and stirred for 16 h after which time the reactionmixture was quenched with dilute HCl and evaporated to dryness. Theresidue was diluted with water and extracted with ethyl acetate. Theethyl acetate layer was washed with water, brine, dried over anhydroussodium sulfate and concentrated under reduced pressure to give the crudeproduct. Purification by preparative HPLC afforded3-fluoro-1,2-dimethyl-4-phenyl-pyrrole (160 mg, 39%) as a solid.

Reference Example 260

The compound set out below was prepared in a manner analogous toReference Example 259.

Reference Example Compound 2603-Fluoro-1-(2-methoxyethyl)-2-methyl-4-phenyl-pyrrole

Reference Example 261 2-(2-Methyl-4-phenyl-pyrrol-1-yl)ethanol

Boron tribromide (0.3 mL, 3.07 mmol) was added drop wise to a solutionof 1-(2-methoxyethyl)-2-methyl-4-phenyl-pyrrole (330 mg, 1.53 mmol) indry dichloromethane (20 mL) at 0 to 5° C. and stirred for 1 h. Thereaction mixture was quenched with a 10% sodium bicarbonate solution (20mL) at 0 to 5° C. and extracted with ethyl acetate (2×25 mL). Theorganic layer was washed successively with water (2×25 mL), brine (2×25mL), dried over anhydrous sodium sulphate and concentrated in vacuo toyield 2-(2-methyl-4-phenyl-pyrrol-1-yl)-ethanol (270 mg, 88%) as a brownsolid.

Reference Examples 262

The compound set out below was prepared in a manner analogous toReference Example 261.

Reference Example Compound 262 2-(3-Phenylpyrrol-1-yl)ethanol

Reference Example 263 2-(2-methyl-4-phenyl-pyrrol-1-yl)ethyl4-methylbenzenesulfonate

Triethylamine (2.1 mL, 15.22 mmol) was added to a solution of2-(2-methyl-4-phenylpyrrol-1-yl)ethanol (1.53 g, 7.61 mmol) in drydichloromethane (20 mL) at room temperature followed by the addition ofp-toluene sulfonyl chloride (1.88 g, 9.89 mmol). The resulting reactionmixture was stirred for 16 h and then diluted with water (30 mL) andextracted with ethyl acetate (2×25 mL). The combined organic layers werewashed with water (2×25 mL), brine (2×25 mL), dried over anhydroussodium sulphate and concentrated in vacuo to yield the crude compound.Purification by column chromatography over silica gel (100-200 mesh)with gradient elution with 10-12% ethyl acetate in petroleum ether aseluent afforded 2-(2-methyl-4-phenyl-pyrrol-1-yl)ethyl4-methylbenzenesulfonate (1.2 g, 44%) as a brownish white crystallinesolid.

Reference Example 264

The compound set out below was prepared in a manner analogous toReference Example 263

Reference Example Compound 264 2-Isopropoxyethyl4-methylbenzenesulfonate

Reference Example 265 1-(2-Azidoethyl)-2-methyl-4-phenyl-pyrrole

Sodium azide (327 mg, 5.02 mmol) was added to a solution of2-(2-methyl-4-phenyl-pyrrol-1-yl)ethyl 4-methylbenzenesulfonate (1.19 g,3.35 mmol) in dry dimethylformamide (10 mL) and heated to 90° C. andstirred for 1 h. The reaction mixture was allowed to cool to ambienttemperature and partitioned between water (20 mL) and ethyl acetate (25mL). After stirring for 5 min, the organic layer was separated andwashed successively with water (2×30 mL), brine (2×30 mL), dried overanhydrous sodium sulphate and concentrated in vacuo to yield1-(2-azidoethyl)-2-methyl-4-phenyl-pyrrole (650 mg, 86%) as a brownliquid.

Reference Example 266 2-(2-Methyl-4-phenyl-pyrrol-1-yl)ethanamine

10% Palladium-carbon (100 mg) was added to a solution of1-(2-azidoethyl)-2-methyl-4-phenyl-pyrrole (640 mg, 2.96 mmol) inmethanol (20 mL) at room temperature and hydrogenated at atmosphericpressure for 27 h. The catalyst was filtered and washed with methanol(20 mL). The combined filtrate and washings were concentrated in vacuoto afford 2-(2-methyl-4-phenyl-pyrrol-1-yl)ethanamine (490 mg, 83%) as abrown syrup.

Reference Example 267

The compound set out below was prepared in a manner analogous toReference Example 266:

Reference Example Compound 267 1-Isobutyl-piperazine

Reference Example 268 2-(2-Methyl-4-phenyl-pyrrol-1-yl)ethyl acetate

Triethylamine (0.5 mL, 3.59 mmol) was added dropwise to a solution of2-(2-methyl-4-phenyl-pyrrol-1-yl)ethanol (260 mg, 1.29 mmol) in drydichloromethane (20 mL) at 0 to 5° C. followed by the addition of acetylchloride (0.2 mL, 2.81 mmol). The reaction mixture was stirred for 30min and then quenched into ice water (30 mL) and ethyl acetate (20 mL)and stirred for 15 min. The organic layer was separated and washed withwater (2×25 mL), brine (2×25 mL), dried over anhydrous sodium sulphateand concentrated in vacuo to afford2-(2-methyl-4-phenyl-pyrrol-1-yl)ethyl acetate (300 mg, 96%) as a brownliquid.

Reference Examples 269 to 270

The compounds set out below were prepared in a manner analogous toReference Example 268:

Reference Example Compound 269N-[2-(2-Methyl-4-phenyl-pyrrol-1-yl)-ethyl]acetamide 2702-(3-Phenyl-pyrrol-1-yl)-ethyl acetate

Reference Example 271 Ethyl 2-(3-Phenylpyrrol-1-yl)acetate

Glycine ethyl ester hydrochloride (0.44 g, 3.17 mmol), sodium acetate(0.47 g, 5.76 mmol) were dissolved in minimum amount of water (5 mL) andadded to glacial acetic acid (5 mL). The mixture was heated to 80° C.and then added to a solution of 2,5-dimethoxy-3-phenyl-tetrahydrofuran(0.6 g, 2.88 mmol) in glacial acetic acid (5 mL). The reaction wasstirred at 80° C. for 2 h and then diluted with water and extracted withethyl acetate. The combined organic layers were washed with copiousamount of water, dried over anhydrous sodium sulfate and concentrated invacuo to afford ethyl 2-(3-phenylpyrrol-1-yl)acetate (0.55 g, 83%).

Reference Example 272 2-(3-Isopropylpyrrol-1-yl)acetic acid

Trifluoroacetic acid (1.20 mL, 15.70 mmol) was added to a solution oftert-butyl 2-(3-isopropyl-pyrrol-1-yl)acetate (350 mg, 1.57 mmol) indichloromethane at 0° C. and the reaction mixture was stirred at ambienttemperature for 16 h. The solvent was evaporated in vacuo and theresidue was basified with saturated sodium bicarbonate solution. Thesolution was washed with diethyl ether and the alkaline solution wasthen acidified with concentrated aqueous HCl and extracted with diethylether. The organic layer was washed with water, brine solution, driedover anhydrous sodium sulfate and concentrated in vacuo to give2-(3-isopropylpyrrol-1-yl)acetic acid (180 mg, 69%) as a semi-solid.

Reference Examples 273 to 275

The compounds set out below were prepared in a manner analogous toReference Example 272:

Reference Example Compound 273 2-(3-Isobutyl-pyrrole-1-yl)acetic acid274 2-(3-Cyclobutylpyrrol-1-yl)acetic acid 2751-(2-Methylallyl)piperazine

Reference Example 276 Methyl 2-(3-Isopropylpyrrol-1-yl)acetate

Potassium carbonate (298 mg, 2.15 mmol) was added to a solution of2-(3-isopropylpyrrol-1-yl)acetic acid (180 mg, 1.07 mmol) in acetone at0° C. and the reaction was stirred at 0° C. for 15 min. Methyl iodide(0.13 mL, 2.15 mmol) was added at 0° C. and the mixture refluxed for 16h. The reaction mixture was concentrated in vacuo and the residue wasdiluted with water and extracted with diethyl ether. The organic layerwas washed with water, brine solution, dried over anhydrous sodiumsulphate, filtered and concentrated in vacuo to give the crude compound.Purification by column chromatography over neutral alumina by using 1-2%ethyl acetate in petroleum ether as eluent afforded methyl2-(3-Isopropylpyrrol-1-yl)acetate (135 mg, 69%) as a liquid.

Reference Examples 277 to 278

The compounds set out below were prepared in a manner analogous toReference Example 276:

Reference Example Compound 277 Methyl 2-(3-Isobutylpyrrol-1-yl)acetate278 Methyl 2-(3-Cyclobutyl-pyrrol-1-yl)acetate

Reference Example 279 Ethyl2-[5-(methoxymethyl)-1-methyl-3-phenyl-pyrrol-2-yl]-2-oxo-acetate

Ethyl chloro oxoacetate (760 mg, 5.59 mmol) was added to a solution of2-methoxymethyl-1-methyl-4-phenyl-pyrrole (750 mg 3.73 mmol) andtriethylamine (490 mg 4.85 mmol) in dichloromethane (10 mL) at 0° C. Themixture was stirred for 4 h then concentrated in vacuo. The resultingresidue was dissolved in dichloromethane and washed with saturatedsodium bicarbonate solution, brine, dried over anhydrous sodium sulfateand concentrated in vacuo to afford the crude product. Purification bycolumn chromatography over neutral alumina using 5-10% ethyl acetate inpetroleum ether as eluent afforded ethyl2-[5-(methoxymethyl)-1-methyl-3-phenyl-pyrrol-2-yl]-2-oxo-acetate (600mg, 53%) as a liquid.

Reference Example 280

The compound set out below was prepared in a manner analogous toReference Example 279:

Reference Example Compound 280 Ethyl2-[1,5-bis(methoxymethyl)-3-phenyl-pyrrol-2-yl]-2- oxo-acetate

Reference Example 2812-[5-(methoxymethyl)-1-methyl-3-phenyl-pyrrol-2-yl]-2-oxo-acetic acid

Lithium hydroxide (170 mg, 4.04 mmol) was added to a solution of ethyl2-[5-(methoxymethyl)-1-methyl-3-phenyl-pyrrol-2-yl]-2-oxo-acetate (600mg, 1.90 mmol) in methanol (20 mL) and stirred for 3 h at ambienttemperature. The mixture was concentrated in vacuo and the residuedissolved in water and acidified with acetic acid. The mixture wasextracted with ethyl acetate, the organic layer washed with brine, driedover anhydrous sodium sulphate and concentrated in vacuo to afford2-[5-(methoxymethyl)-1-methyl-3-phenyl-pyrrol-2-yl]-2-oxo-acetic acid(350 mg, 64%) as a solid.

Reference Examples 282 to 283

The compounds set out below were prepared in a manner analogous toReference Example 281:

Reference Example Compound 2822-[1,5-Bis(methoxymethyl)-3-phenyl-pyrrol-2-yl]-2-oxo-acetic acid 2832-[1-(2-Methoxyethyl)-3-(3-thienyl)pyrrol-2-yl]-2-oxo-acetic acid

Reference Example 284 2-(1,5-Dimethyl-3-phenyl-pyrrol-2-yl)-2-oxo-acetylchloride

Oxalyl chloride (19.5 mL, 0.21 mol) was added slowly to a 0° C. solutionof 1,2-dimethyl-4-phenyl-pyrrole (30.5 g, 0.178 mol) in drydichloromethane (150 mL). The reaction mixture was warmed to roomtemperature and stirred for 1 h. The solvent was removed in vacuo toafford 2-(1,5-dimethyl-3-phenyl-pyrrol-2-yl)-2-oxo-acetyl chloride (46g, 99%) as a brown oil.

Reference Examples 285 to 348

The compounds set out below were prepared in a manner analogous toReference Example 284:

Reference Example Compound 285 2-Oxo-(1-phenylpyrrol-2-yl)acetylchloride 286 2-(5-Methyl-1-phenylpyrrol-2-yl)-2-oxo-acetyl chloride 2872-(5-Methyl-1H-pyrrol-2-yl)-2-oxo-acetyl chloride 2882-(2-Methyl-7-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazin-6-yl)-2-oxo-acetyl chloride 2892-Oxo-2-(2-phenyl-6,7-dihydro-5H-pyrrolizin-3- yl)acetyl chloride 2902-Oxo-2-(7-phenyl-3,4-dihydro-1H-pyrrolo[2,1- c][1,4]oxazin-6-yl)acetylchloride 291 2-(1-Isopropyl-5-methyl-3-phenyl-pyrrol-2-yl)-2-oxo- acetylchloride 292 2-[1-(2-Methoxyethyl)-5-methyl-3-phenyl-pyrrol-2-yl]-2-oxo-acetyl chloride 2932-[3-(2-Furyl)-1,5-dimethyl-pyrrol-2-yl]-2-oxo-acetyl chloride 2942-[1,5-Dimethyl-3-(2-thienyl)pyrrol-2-yl]-2-oxo-acetyl chloride 2952-(3-Isopropyl-1,5-dimethyl-pyrrol-2-yl)-2-oxo-acetyl chloride 2962-(1,5-Dimethyl-3-tetrahydropyran-4-yl-pyrrol-2-yl)-2- oxo-acetylchloride 297 2-(1,4-Dimethyl-3-phenyl-pyrrol-2-yl)-2-oxo-acetyl chloride(obtained as a mixture with the regioisomer 2-(1,3-dimethyl-4-phenyl-1H-pyrrol-2-yl)-2-oxo-acetyl chloride) 2982-(5-Isopropyl-1-methyl-3-phenyl-pyrrol-2-yl)-oxo- acetyl chloride 2992-[3-Isopropyl-1-(2-methoxyethyl)-5-methyl-pyrrol-2- yl]-2-oxo-acetylchloride 300 2-[1-(2-Ethoxyethyl)-5-methyl-3-phenyl-pyrrol-2-yl]-2-oxo-acetyl chloride 3012-[1-(3-Methoxypropyl)-5-methyl-3-phenyl-pyrrol-2- yl]-2-oxo-acetylchloride 302 2-(5-Ethyl-1-methyl-3-phenyl-pyrrol-2-yl)-2-oxo-acetylchloride 303 2-[5-Ethyl-1-(2-methoxyethyl)-3-phenyl-pyrrol-2-yl]-2-oxo-acetyl chloride 304 Ethyl2-(2-chloro-2-oxo-acetyl)-5-methyl-3-phenyl- pyrrole-1-carboxylate 305Methyl 2-(2-chloro-2-oxo-acetyl)-5-methyl-3-phenyl-pyrrole-1-carboxylate 3062-[3-(2-Chlorophenyl)-1-(2-methoxyethyl)pyrrol-2-yl]- 2-oxo-acetylchloride 307 2-[4-(2-Chlorophenyl)-1-(2-methoxyethyl)pyrrol-2-yl]-2-oxo-acetyl chloride 3082-[3-(4-Chlorophenyl)-1-(2-methoxyethyl)pyrrol-2-yl]- 2-oxo-acetylchloride 309 Methyl 2-[2-(2-chloro-2-oxo-acetyl)pyrrol-1-yl]acetate 3102-[1-(Methoxymethyl)-3-phenyl-pyrrol-2-yl]-2-oxo- acetyl chloride &2-[l-(Methoxymethyl)-4-phenyl-1H- pyrrol-2-yl)-2-oxo-acetyl chloride 3112-[2-(2-Chloro-2-oxo-acetyl)-5-methyl-3-phenyl-pyrrol- 1-yl]acetate 3122-[1-(2-Acetamidoethyl)-5-methyl-3-phenyl-pyrrol-2- yl]-2-oxo-acetylchloride 313 2-[1-(2-Methoxyethyl)-3-(2-thienyl)pyrrol-2-yl]-2-oxo-acetyl chloride 314 2-[3-Isobutyl-1-(2-methoxyethyl)pyrrol-2-yl]-2-oxo-acetyl chloride 3152-[3-(3-Chlorophenyl)-1-(2-methoxyethyl)pyrrol-2-yl]- 2-oxo-acetylchloride & 2-[4-(3-Chlorophenyl)-1-(2-methoxyethyl)pyrrol-2-yl]-2-oxo-acetyl chloride 316 Ethyl2-[2-(2-chloro-2-oxo-acetyl)-3-phenyl-pyrrol-1- yl]acetate 317 Methyl2-[2-(2-chloro-2-oxo-acetyl)-3-phenyl-pyrrol-1- yl] acetate & methyl2-[2-(2-chloro-2-oxo-acetyl)-4- phenyl-pyrrol-1-yl]acetate 318 Isopropyl2-[2-(2-chloro-2-oxo-acetyl)-5-methyl-3- phenyl-pyrrol-1-yl]acetate 3192-[5-Isopropyl-1-(2-methoxyethyl)-3-phenyl-pyrrol-2- yl]-2-oxo-acetylchloride 320 2-[3-(2-Methoxyethyl)-5-methyl-1-phenyl-pyrrol-2-yl]-2-oxo-acetyl chloride 3212-[1-(2-Methoxyethyl)-3-phenyl-pyrrol-2-yl]-2-oxo- acetyl chloride 3222-[3-Isopropyl-1-(2-methoxyethyl)pyrrol-2-yl]-2-oxo- acetyl chloride 3232-[1-(2-Dimethylaminoethyl)-3-phenyl-pyrrol-2-yl]-2- oxo-acetyl chloride324 2-[1-(2-Dimethylaminoethyl)-4-phenyl-pyrrol-2-yl]-2- oxo-acetylchloride 325 2-[1-(2-Dimethylaminoethyl)-5-methyl-3-phenyl-pyrrol-2-yl]-2-oxo-acetyl chloride 326 Methyl2-[2-(2-chloro-2-oxo-acetyl)-3-(2-thienyl)pyrrol- 1-yl] acetate 327Methyl 2-[2-(2-chloro-2-oxo-acetyl)-3-isopropyl-pyrrol- 1-yl]acetate 328Methyl 2-[2-(2-chloro-2-oxo-acetyl)-3-isobutyl-pyrrol-1- yl]acetate 3292-(4-Fluoro-1,5-dimethyl-3-phenyl-pyrrol-2-yl)-2-oxo- acetyl chloride330 2-[5-Methyl-3-phenyl-1-(2-pyridylmethyl)pyrrol-2-yl]- 2-oxo-acetylchloride 331 2-[5-Methyl-3-phenyl-1-(3-pyridylmethyl)pyrrol-2-yl]-2-oxo-acetyl chloride 3322-[4-Fluoro-1-(2-methoxyethyl)-5-methyl-3-phenyl-pyrrol-2-yl]-2-oxo-acetyl chloride 3332-[1-(2-Isopropoxyethyl)-5-methyl-3-phenyl-pyrrol-2- yl]-2-oxo-acetylchloride 334 2-[5-Methyl-3-phenyl-1-(4-pyridylmethyl)pyrrol-2-yl]-2-oxo-acetyl chloride 3352-[3-Cyclobutyl-1-(2-methoxyethyl)pyrrol-2-yl]-2-oxo- acetyl chloride336 Methyl 2-[2-(2-chloro-2-oxo-acetyl)-3-cyclobutyl-pyrrol-1-yl]acetate 3372-(1-Methyl-3-phenyl-5-propyl-pyrrol-2-yl)-2-oxo- acetyl chloride 3382-[5-Ethyl-1-(methoxymethyl)-3-phenyl-pyrrol-2-yl]-2- oxo-acetylchloride 339 2-[1-(Ethoxymethyl)-5-methyl-3-phenyl-pyrrol-2-yl]-2-oxo-acetyl chloride 3402-[5-Methyl-1-(2-methylsulfanylethyl)-3-phenyl-pyrrol-2-yl]-2-oxo-acetyl chloride 3412-[1-(3-Ethoxypropyl)-5-methyl-3-phenyl-pyrrol-2-yl]- 2-oxo-acetylchloride 342 2-[1-(2-Methoxyethoxymethyl)-5-methyl-3-phenyl-pyrrol-2-yl]-2-oxo-acetyl chloride 3432-[5-Methyl-3-phenyl-1-(propoxymethyl)pyrrol-2-yl]-2- oxo-acetylchloride 344 2-[5-Methyl-1-(2-phenoxyethyl)-3-phenyl-pyrrol-2-yl]-2-oxo-acetyl chloride 3452-[5-Methyl-3-phenyl-1-(2-propoxyethyl)pyrrol-2-yl]-2- oxo-acetylchloride 346 2-[1-(4-Methoxybut-2-enyl)-5-methyl-3-phenyl-pyrrol-2-yl]-2-oxo-acetyl chloride 3472-[1-(4-Methoxybutyl)-5-methyl-3-phenyl-pyrrol-2-yl]- 2-oxo-acetylchloride 348 2-[1-(Butoxymethyl)-5-methyl-3-phenyl-pyrrol-2-yl]-2-oxo-acetyl chloride

Reference Example 349 Ethyl2-[1-(2-methoxyethyl)-3-(3-thienyl)pyrrol-2-yl]-2-oxo-acetate

Chloroethyl oxalate (0.13 mL, 1.18 mmol) was added slowly to a cooledsolution of 1-(2-methoxy-ethyl)-3-thiophen-2-yl-1H-pyrrole (300 mg, 1.55mmol) and triethylamine (0.28 mL) in dry dichloromethane (15 mL) at 0°C. The reaction mixture was allowed to warm to ambient temperature andstirred for 16 h. The solvent was removed in vacuo to afford ethyl2-[1-(2-methoxyethyl)-3-(3-thienyl)pyrrol-2-yl]-2-oxo-acetate (250 mg,85%) as a brown oily liquid.

Reference Example 350 2-Chloro-4,6-dimethyl-pyridine

A mixture of 2-amino-4,6-dimethylpyridine (90 g, 0.736 mol) and sodiumchloride (216 g, 3.69 mol) in concentrated hydrochloric acid (720 mL)was cooled to between −15 and −20° C. A solution of sodium nitrite (71.2g, 1.03 mol) in water (135 mL) was added over 30 min. More sodiumchloride (216 g, 3.69 mol) was added and the reaction mixture wasallowed to warm to ambient temperature and stirred for 1 h. The reactionmixture was basified with solid bicarbonate (700 g) and extracted withdichloromethane (1 L), filtered and the two phases separated. Theorganic layer was concentrated in vacuo and the crude purified by flashcolumn chromatography over silica gel (100-200 mesh) with 20%dichloromethane in petroleum ether as eluent to afford2-chloro-4,6-dimethylpyridine (40 g, 38%) as a solid.

Reference Example 351 1-(4,6-dimethyl-2-pyridyl)piperazine

A solution of piperazine (195 g, 2.26 mol) in diglyme (250 mL) washeated to 160° C. and a solution of 2-chloro-4,6-dimethylpyridine (40 g,0.283 mol) in diglyme (150 mL) was added over a period of 30 min. Themixture was maintained at this temperature for 36 hand then the reactionmixture was allowed to cool to ambient temperature, diluted with brineand extracted with ethyl acetate (3×500 mL). The combined organic layerswere washed with brine (2×100 mL), dried over anhydrous sodium sulfateand concentrated in vacuo to give the crude compound. Vacuumdistillation to remove diglyme afforded1-(4,6-dimethyl-2-pyridyl)piperazine (50 g, 92%) as an oil.

Reference Examples 352 to 354

The compounds set out below were prepared in a manner analogous toReference Example 351:

Reference Example Compound 352 1-(2-Pyridyl)piperazine 3531-(6-Methyl-2-pyridyl)piperazine 354 1-(4-Methyl-2-pyridyl)piperazine

Reference Example 3551-(4,6-dimethyl-2-pyridyl)-4-(4-nitrophenyl)piperazine

A solution of 1-(4,6-dimethyl-2-pyridyl)piperazine (52 g, equivalent to50.0 g after correcting for residual diglyme determined by GC analysis,265 mmol) and potassium carbonate (72.4 g, 523 mmol) in diglyme (150 mL)was stirred at room temperature for 15 min and then heated to 150° C. Asolution of 1-chloro-4-nitro-benzene (62 g, 392 mmol) in diglyme (150mL) was added over 15 min and the mixture heated at reflux for 46 h. Thereaction mixture was allowed to cool to ambient temperature and filteredto remove insoluble salts and the filter cake was washed with ethylacetate (2×250 mL). The filtrate was concentrated in vacuo to give aviscous oil, to which was added 3N hydrochloric acid (650 mL). Afterstirring for 1 h the precipitated solid was filtered off and washed withwater (100 mL). This solid was stirred in ethyl acetate (500 mL) for 30min and filtered. The process was repeated once more yielding the crudeproduct as its hydrochloride salt (85 g). The salt was suspended inwater (1.0 L), basified to pH ˜9 with ammonium hydroxide (100 mL) andextracted with dichloromethane (2×750 mL). The combined organic layerswere washed with brine (2×250 mL), dried and evaporated to dryness toafford 1-(4,6-dimethyl-2-pyridyl)-4-(4-nitrophenyl)piperazine (49 g,60%) as a solid.

Reference Examples 356 to 360

The compounds set out below were prepared in a manner analogous toReference Example 355:

Reference Example Compound 356[2-[4-(4,6-Dimethyl-2-pyridyl)piperazin-1-yl]-5-nitro- phenyl]methanol357 1-(2-Chloro-4-nitro-phenyl)-4-(4,6-dimethyl-2- pyridyl)piperazine358 5-[4-(4,6-Dimethyl-2-pyridyl)piperazin-1-yl]-2-nitro-aniline 3591-Methyl-4-(5-nitro-1-naphthyl)piperazine 3601-(4,6-Dimethyl-2-pyridyl)-4-(2-methyl-4-nitro- phenyl)piperazine

Reference Example 361 2-Chloro-5-nitro-phenol

A saturated solution of sodium nitrite (1.8 g, 26.0 mmol) in water (12mL) was added dropwise to a suspension of 2-amino-5-nitro-phenol (2.0 g,13.0 mmol) in concentrated hydrochloric acid (10 mL) at 0° C. andstirred for 30 min. A solution of Copper (I) chloride (5.15 g, 52.0mmol) and concentrated hydrochloric acid (20 mL) heated to between 60and 70° C. was added dropwise over a period of 30 min. The resultantreaction mixture was heated to 80° C. and stirred for 15 min and thenallowed to cool to ambient temperature. Ethyl acetate (50 mL) was addedand after stirring for 5 min the organic phase was separated and theaqueous phase was re-extracted with ethyl acetate (2×50 mL). Thecombined organic phases were washed with water (4×50 mL), brine, driedover anhydrous sodium sulfate and concentrated in vacuo to give aresidue which was purified by column chromatography over silica gel(100-200 mesh) using 5% ethyl acetate in petroleum ether as eluent toafford 2-chloro-5-nitro-phenol (2.08 g, 92%) as a crystalline yellowsolid.

Reference Example 362 1-Fluoro-5-nitro-naphthalene

Sodium nitrite (660 mg, 9.57 mmol) was added portionwise to a suspensionof 5-nitronaphthalen-1-amine (1.2 g, 6.38 mmol) in a 1:1 mixture ofwater/concentrated hydrochloric acid (10 mL) at −5° C. The mixture wasstirred for 15 min at −5° C. and a 60% w/w hexafluoro phosphoric acidsolution (6 mL) was added. The brown precipitate was filtered and washedwith cold water and diethyl ether and then allowed to dry in vacuo. Theresulting solid was suspended in toluene and heated to 110° C. for 2 hbefore the mixture was then allowed to cool to ambient temperature andthe solvent removed in vacuo to afford the crude product. Purificationby column chromatography over silica gel (100-200 mesh) using petroleumether as eluent afforded 1-fluoro-5-nitro-naphthalene (450 mg, 37%) as ayellow solid.

Reference Example 363 2-Benzyloxy-1-chloro-4-nitro-benzene

Benzyl bromide (0.6 mL, 5.04 mmol) was added dropwise to a mixture of2-chloro-5-nitro-phenol (800 mg, 4.61 mmol) and potassium carbonate(1.27 g, 9.22 mmol) in acetone (20 mL) at ambient temperature and thenheated at reflux for 2 h. The inorganic residue was filtered off andwashed with acetone (20 mL). The combined filtrate and washings wereconcentrated in vacuo and the resulting residue was then dissolved inethyl acetate (25 mL) and washed successively with water (2×20 mL),brine (20 mL), dried over anhydrous sodium sulfate and concentrated invacuo to yield 2-benzyloxy-1-chloro-4-nitro-benzene (1.20 g, 99%) as acream solid.

Reference Example 3641-(2-Benzyloxy-4-nitro-phenyl)-4-(4,6-dimethyl-2-pyridyl)piperazine

A mixture of 2-benzyloxy-1-chloro-4-nitro-benzene (700 mg, 2.66 mmol),1-(4,6-dimethyl-pyridin-2-yl)-piperazine (457 mg, 2.39 mmol) and caesiumcarbonate (2.58 g, 7.97 mmol) in toluene (30 mL) was purged with argongas. Palladium acetate (24 mg, 0.106 mmol) and2-(dicyclohexylphosphino)-2′-N,N-dimethylamino)-biphenyl (42 mg, 0.106mmol) were added. After purging again with argon gas the reactionmixture was heated at reflux for 20 h. The reaction mixture was cooled,filtered and the filter cake was washed with ethyl acetate (30 mL). Thecombined filtrate and washings were washed successively with water (2×50mL), brine (2×50 mL), dried over anhydrous sodium sulfate andconcentrated in vacuo to yield a residue which was purified by flashcolumn chromatography over silica gel (100-200 mesh) using 8-10% ethylacetate in petroleum ether as eluent to afford1-(2-benzyloxy-4-nitro-phenyl)-4-(4,6-dimethyl-2-pyridyl)piperazine (510mg, 46%) as a pale yellow solid.

Reference Example 3654-[3-[[2-[4-(4,6-Dimethyl-2-pyridyl)piperazin-1-yl]-5-nitro-phenyl]methoxy]propyl]morpholine

Aqueous sodium hydroxide (50% w/w, 10 g, 125 mmol) andtetrabutylammonium hydrogen sulfate (0.20 g) were added successively toa solution of[2-[4-(4,6-dimethyl-2-pyridyl)piperazin-1-yl]-5-nitro-phenyl]methanol(0.50 g, 1.46 mmol) in toluene (5 mL). The mixture was heated to refluxwith vigorous stirring for 45 min then 4-(3-chloro-propyl)-morpholine(0.50 g, 3.00 mmol) was added and reflux continued for 28 h. Thereaction mixture was cooled and the organic phase separated. The aqueousphase was extracted with ethyl acetate (3×5 mL). The organic phases werecombined, washed with water and brine, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum to give a residue whichwas purified by preparative TLC eluting with 2% methanol in chloroformto afford4-[3-[[2-[4-(4,6-dimethyl-2-pyridyl)piperazin-1-yl]-5-nitro-phenyl]methoxy]propyl]morpholine(550 mg, 80%) as a solid.

Reference Examples 366 and 367

The compounds set out below were prepared in a manner analogous toReference Example 365.

Reference Example Compound 3662-[[2-[4-(4,6-Dimethyl-2-pyridyl)piperazin-1-yl]-5-nitro-phenyl]methoxy]-N,N-dimethyl-ethanamine 3671-(4,6-Dimethyl-2-pyridyl)-4-[2-[3-(4-methylpiperazin-1-yl)propoxymethyl]-4-nitro-phenyl]piperazine

Reference Example 3681-(3-chloro-4-nitro-phenyl)-4-(4,6-dimethyl-2-pyridyl)piperazine

50% Aqueous hydrochloric acid (30 mL) was cooled to −20° C.,5-[4-(4,6-dimethyl-2-pyridyl)piperazin-1-yl]-2-nitro-aniline (1.4 g,4.28 mmol) was added and the reaction mixture stirred for 15 min. Asolution of sodium nitrite (350 mg, 5.14 mmol) in water (8 mL) was addedand the reaction mixture stirred for 15 min. This solution was addeddropwise to a cooled solution of copper (I) chloride (635 mg, 6.42 mmol)in 50% hydrochloric acid (20 mL) over a period of 20 min and stirred fora further 10 min before basifying with saturated sodium carbonatesolution. The mixture was extracted with ethyl acetate and the organicphase was washed with water, brine, dried over anhydrous sodium sulfateand concentrated under vacuum to give a crude residue. Purification bycolumn chromatography over silica gel (100-200 mesh) using 8% ethylacetate in petroleum ether as eluent afforded1-(3-chloro-4-nitro-phenyl)-4-(4,6-dimethyl-pyridin-2-yl)-piperazine1-(3-chloro-4-nitro-phenyl)-4-(4,6-dimethyl-2-pyridyl)piperazine (800mg, 54%) as a yellow solid.

Reference Example 3692-[4-(4,6-dimethyl-2-pyridyl)piperazin-1-yl]-5-nitro-phenol

Trifluoroacetic acid (5 mL) was added to1-(2-benzyloxy-4-nitro-phenyl)-4-(4,6-dimethyl-2-pyridyl)piperazine (720mg, 1.72 mmol) at between 0 and 5° C. followed by concentratedhydrochloric acid (2 mL). The mixture was heated at reflux for 16 h thencooled to between 0 and 5° C. and quenched with saturated sodiumbicarbonate solution (30 mL). Chloroform (30 mL) was added and themixture was stirred for 15 min. The organic phase was separated and theaqueous phase was extracted with chloroform (30 mL). The combinedorganic phases were washed with water (2×30 mL), brine (30 mL), driedover anhydrous sodium sulfate and concentrated in vacuo to give a cruderesidue. Trituration with petroleum ether afforded2-[4-(4,6-dimethyl-2-pyridyl)piperazin-1-yl]-5-nitro-phenol (510 mg,90%) as a brownish-yellow solid.

Reference Example 370[2-[4-(4,6-dimethyl-2-pyridyl)piperazin-1-yl]-5-nitro-phenyl]acetate

Triethylamine (1.0 mL, 7.17 mmol) was added to a solution of2-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-5-nitro-phenol (500 mg,1.52 mmol) in dry dichloromethane (20 mL) followed by the dropwiseaddition of acetyl chloride (0.2 mL, 2.80 mmol). After stirring for 15min, water was added and the mixture warmed to room temperature. Theorganic phase was separated and the aqueous phase was extracted withdichloromethane (2×30 mL). The combined organic phases were washed withwater (2×30 mL), brine (2×30 mL), dried over anhydrous sodium sulfateand concentrated in vacuo. The residue was triturated with 5%dichloromethane in petroleum ether (2×20 mL) to afford[2-[4-(4,6-dimethyl-2-pyridyl)piperazin-1-yl]-5-nitro-phenyl]acetate(365 mg, 65%) as a pale brownish-yellow solid.

Reference Example 371

The compound set out below was prepared in a manner analogous toReference Example 370.

Reference Example Compound 371N-[2-(2-Methyl-4-phenyl-pyrrol-1-yl)ethyl]acetamide

Reference Example 372 2-(Bromomethyl)-1-methoxy-3-nitro-benzene

N-bromosuccinimide (590 mg, 3.30 mmol) was added to a solution of1-methoxy-2-methyl-3-nitro-benzene (500 mg, 3.0 mmol) in carbontetrachloride (5 mL) followed by a catalytic amount of dibenzoylperoxide (25 mg). The reaction mixture was heated at reflux for 3 h thencooled to room temperature and poured into water. The organic phase wasseparated, washed with water (2×20 mL), dried over the anhydrous sodiumsulfate and concentrated in vacuo to afford2-(bromomethyl)-1-methoxy-3-nitro-benzene (640 mg, 86%) as a solid.

Reference Example 373 2-(2-Methoxy-6-nitro-phenyl)acetonitrile

Sodium cyanide (165 mg, 3.36 mmol) was added to a solution of2-(bromomethyl)-1-methoxy-3-nitro-benzene (680 mg, 2.56 mmol) in ethanol(5 mL) and the mixture was heated at reflux for 16 h. The solvent wasremoved in vacuo, water (30 mL) was added and the mixture was extractedwith dichloromethane (25 mL). The organic phase was washed with water(2×20 mL), brine (20 mL), dried over anhydrous sodium sulfate andconcentrated in vacuo. The crude compound was purified by columnchromatography over silica gel (100-200 mesh) using 8% ethyl acetate inpetroleum ether to afford 2-(2-methoxy-6-nitro-phenyl)acetonitrile (300mg, 61%).

Reference Example 374 Ethyl 2-(2-methoxy-6-nitro-phenyl)acetate

Concentrated sulfuric acid (1 mL) was slowly added to a solution of2-(2-methoxy-6-nitro-phenyl)acetonitrile (200 mg, 1.04 mmol) in 95%ethanol (2 mL). The mixture was heated at reflux overnight then quenchedinto ice cold water and extracted with diethyl ether (10 mL). Theorganic phase was washed with water (2×10 mL), dried over anhydroussodium sulfate and concentrated in vacuo to afford ethyl2-(2-methoxy-6-nitro-phenyl)acetate (180 mg, 72%).

Reference Example 375 2-(2-Methoxy-6-nitro-phenyl)ethanol

Diisobutylaluminium hydride (20 wt %; 2.38 g, 16.8 mmol) in toluene wasadded to a solution of 2-(2-methoxy-6-nitro-phenyl)acetate (1.0 g, 4.18mmol) in tetrahydrofuran (8 mL) at −5° C. The reaction mixture wasstirred at 0° C. for 1 h and then poured into 1N hydrochloric acid. Themixture was extracted with ethyl acetate (30 mL) and the separatedorganic phase was washed with water (2×30 mL), brine (25 mL), dried overanhydrous sodium sulfate and concentrated in vacuo to afford2-(2-methoxy-6-nitro-phenyl)ethanol (780 mg, 94%).

Reference Example 376 [1-(methoxymethyl)-4-phenyl-pyrrol-2-yl]methanol

Lithium aluminum hydride (113 mg, 3.06 mmol) was added portionwise to astirred solution of methyl1-(methoxymethyl)-4-phenyl-pyrrole-2-carboxylate (500 mg, 2.04 mmol) intetrahydrofuran (10 mL) over a period of 15 min at 0° C. The resultingmixture stirred for 12 h and then quenched with ice and the mixtureextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate and concentrated invacuo to yield [1-(methoxymethyl)-4-phenyl-pyrrol-2-yl]methanol (400 mg,91%) as a brown liquid.

Reference Example 377 4-Nitro-2,3-dihydrobenzofuran

2-(2-Methoxy-6-nitro-phenyl)ethanol (700 mg, 3.55 mmol) was dissolved inpolyphosphoric acid (3 mL) and heated at 120° C. for 1 h. After coolingto ambient temperature, ice-water water was added and the mixture wasextracted with ethyl acetate. The organic phase was washed with water(2×20 mL), dried over anhydrous sodium sulfate and concentrated in vacuoto afford 4-nitro-2,3-dihydrobenzofuran (400 mg, 68%).

Reference Example 378 1-(4-nitrophenyl)-4-(2-pyridyl)piperazine

A mixture of 1-chloro-4-nitro-benzene (4.34 g, 27.6 mmol) and anhydrouspotassium carbonate (5.08 g, 36.8 mmol) was added to a solution of1-(2-pyridyl)piperazine (3.0 g, 18.4 mmol) in diglyme (10 mL) and heatedat reflux for 24 h. The reaction mixture was cooled to ambienttemperature, filtered and the filtrate was concentrated in vacuo. Theresidue was diluted with chloroform and the organic layer was washedwith water (5×40 mL), brine (3×30 mL), dried over anhydrous sodiumsulphate and concentrated to yield a crude compound. This was purifiedby washing with hexane (5×5 mL) and then pentane (2×5 mL) to afford1-(4-nitrophenyl)-4-(2-pyridyl)piperazine (4.0 g, 77%) as a yellowsolid.

Reference Examples 379 to 381

The compounds set out below were prepared in a manner analogous toReference Example 378:

Reference Example Compound 3791-(6-Methyl-2-pyridyl)-4-(4-nitrophenyl)piperazine 3801-(4-Methyl-2-pyridyl)-4-(4-nitrophenyl)piperazine 3816-[4-(4-Nitrophenyl)piperazin-1-yl]pyridine-3-carbaldehyde

Reference Example 3824-[[6-[4-(4-nitrophenyl)piperazin-1-yl]-3-pyridyl]methyl]morpholine

Morpholine (250 mg, 2.87 mmol) was added to a suspension of6-[4-(4-nitrophenyl)piperazin-1-yl]pyridine-3-carbaldehyde (750 mg, 2.41mmol) and sodium cyanoborohydride (454 mg, 7.23 mmol) in a mixture oftetrahydrofuran (10 mL) and acetic acid (0.5 mL) at ambient temperaturethen heated at reflux for 3 h. The mixture was then concentrated invacuo to give a gummy solid which was dissolved in chloroform (40 mL),washed with water (2×20 mL), brine (2×15 mL), dried over anhydroussodium sulfate and concentrated in vacuo to give the crude compound.Purification by column chromatography over neutral alumina using 20-30%of ethyl acetate in petroleum ether afforded4-[[6-[4-(4-nitrophenyl)piperazin-1-yl]-3-pyridyl]methyl]morpholine (550mg, 59%).

Reference Example 383 1-(2-fluoro-4-nitro-phenyl)piperidine

Piperidine (0.80 g, 9.42 mmol) was added to a solution of3,4-difluoro-nitro benzene (1.0 g, 6.28 mmol) in acetonitrile (15 mL)and diisopropyl ethylamine (1.62 g, 12.57 mmol) and the mixture wasrefluxed for 3 h. The acetonitrile was removed in vacuo and the residuewas diluted with water and extracted with ethyl acetate. The combinedorganic extracts were washed with brine, dried over anhydrous sodiumsulphate and concentrated in vacuo to afford1-(2-fluoro-4-nitro-phenyl)piperidine (1.3 g, 92%) as a yellow liquid.

Reference Examples 384 to 388

The compounds set out below were prepared in a manner analogous toReference Example 383:

Reference Example Compound 3841-(2-Fluoro-4-nitro-phenyl)-4-(2-pyridyl)piperazine 3851-(2-Fluoro-4-nitro-phenyl)-4-isobutyl-piperazine 3864-(2-Fluoro-4-nitro-phenyl)morpholine 387 1-(4-Nitrophenyl)piperidine388 4-(4-Nitrophenyl)morpholine

Reference Example 389 1-Benzyl-4-(4-nitrophenyl)piperazine

Benzyl bromide (1.42 mL, 11.6 mmol) was added to a solution of1-(4-nitrophenyl)piperazine (2.0 g, 11.6 mmol) in acetonitrile (30 mL)with triethylamine (2.68 mL, 19.32 mmol) and refluxed for 12 h. Themixture was concentrated in vacuo and the residue partitioned betweenwater and ethyl acetate. The organic layer was separated, washed withbrine, dried over anhydrous sodium sulfate and concentrated in vacuo toafford 1-benzyl-4-(4-nitrophenyl)piperazine (2.2 g, 77%).

Reference Example 390 1-(1,2-Dimethylpropyl)-4-(4-nitrophenyl)piperazine

3-Methyl-2-butanone (0.76 mL, 7.24 mmol) was added to a solution of1-(4-nitrophenyl)piperazine (1.0 g, 4.83 mmol) in methanol (10 mL) andacetic acid (1 mL) and stirred for 30 min at ambient temperature. Sodiumcyanoborohydride (1.81 g, 28.98 mmol) was added and the mixture refluxedfor 12 h, cooled and then poured into water and extracted with ethylacetate. The combined organic layers were washed with water, brine,dried over anhydrous sodium sulfate and concentrated in vacuo to affordthe crude product. Purification by column chromatography over silica gel(100-200 mesh) using 5-10% ethyl acetate/petroleum ether as eluentafforded 1-(1,2-Dimethylpropyl)-4-(4-nitrophenyl)piperazine (0.46 g,34%).

Reference Examples 391 to 392

The compounds set out below were prepared in a manner analogous toReference Example 390:

Reference Example Compound 3911-(2-Methoxy-1-methyl-ethyl)-4-(4-nitrophenyl)piperazine 3921-[2-(2-Furyl)-1-methyl-ethyl]-4-(4-nitrophenyl)piperazine

Reference Example 393 2-(4-Nitrophenyl)-5-(1-piperidylmethyl)oxazole

5-(Bromomethyl)-2-(4-nitrophenyl)oxazole (800 mg, 2.82 mmol) was heatedwith piperidine (10 mL) in a sealed tube at 100-110° C. for 12 h. Theresulting mixture was allowed to cool ambient temperature and thenpoured into water (30 0 mL) and stirred for 30 min. The resultant solidwas filtered and washed with water to remove excess piperidine. Theresidue was dried to give 2-(4-nitrophenyl)-5-(1-piperidylmethyl)oxazole(700 mg, 86%) as light orange colour solid.

Reference Example 394 4-Nitro-N-prop-2-ynyl-benzamide

To a stirred solution of propargylamine hydrochloride (5.0 g, 54.6 mmol)and pyridine (7.8 g, 99.1 mmol) in tetrahydrofuran (30 mL) was added4-nitro-benzoylchloride (9.2 g, 49.6 mmol) in tetrahydrofuran (20 mL)and the mixture was heated at reflux for 16 h. The mixture was allowedto cool to ambient temperature and concentrated in vacuo. The cruderesidue was dissolved in ethyl acetate and washed with saturated aqueoussodium bicarbonate solution, water, brine, dried over anhydrous sodiumsulphate, filtered and concentrated in vacuo to afford4-nitro-N-prop-2-ynyl-benzamide (7.74 g, 77%) as a solid.

Reference Example 395 5-Methyl-2-(4-nitrophenyl)oxazole

To a stirred solution of 4-nitro-N-prop-2-ynyl-benzamide (7.5 g, 36.7mmol) in ethanol (150 mL) was added a solution of potassium hydroxide(4.1 g, 73.4 mmol) in ethanol (100 mL) and the mixture was stirred at50-55° C. for 12 h. The mixture was acidified with acetic acid andconcentrated to dryness in vacuo at 45-50° C. The resultant residue wasextracted into ethyl acetate and the separated organic phase was washedwith water; aqueous sodium bicarbonate, brine, dried over anhydroussodium sulphate and concentrated in vacuo to afford5-methyl-2-(4-nitrophenyl)oxazole (3.47 g, 46%) as an oil.

Reference Example 396 Preparation of5-(Bromomethyl)-2-(4-nitrophenyl)oxazole

To a stirred solution of 5-methyl-2-(4-nitrophenyl)oxazole (3.2 g, 15.68mmol) and benzoyl peroxide (10 mg, catalytic) in carbon tetrachloride(20 mL), was added N-bromo succinamide (2.77 g, 15.68 mmol). The mixturewas heated to reflux for 9 h, filtered and the residue was washed withcarbon tetrachloride. The combined filtrates were washed with water,sodium bicarbonate solution, brine, dried over anhydrous sodium sulphateand concentrated in vacuo. The crude product was purified over silicagel (60-120 mesh) with 30% ethyl acetate/hexane as eluent to afford5-(bromomethyl)-2-(4-nitro-phenyl)-oxazole (2.9 g, 65%) as a solid.

Reference Example 3972-Methyl-1-[4-(4-nitrophenyl)piperazin-1-yl]propan-1-one

Triethylamine (976 mg, 9.66 mmol) was added to a solution of1-(4-nitrophenyl)piperazine (1.00 g, 4.83 mmol) in dichloromethane (20mL) at 0° C. and stirred for 30 min. Isobutyryl chloride (617 mg, 5.79mmol) was then added and the mixture was warmed to ambient temperatureand stirred for 4 h. the reaction mixture was quenched with ice-waterand the organic layer separated. The aqueous layer was extracted withdichloromethane (5×5 mL) and the combined organic layers were washedwater, saturated sodium bicarbonate solution, brine, dried overanhydrous sodium sulphate and concentrated in vacuo to afford2-methyl-1-[4-(4-nitrophenyl)piperazin-1-yl]propan-1-one (1.20 g, 90%)as a yellow solid.

Reference Example 3984-[4-(4,6-dimethyl-2-pyridyl)piperazin-1-yl]aniline

A solution of 1-(4,6-dimethyl-2-pyridyl)-4-(4-nitrophenyl)piperazine (49g, 157 mmol) in methanol was hydrogenated over Raney Nickel (15 g) at 90psi pressure for 36 h. The mixture was filtered through Celite and thefiltrate was concentrated in vacuo giving a crude product which waswashed with petroleum ether (100 mL) to afford4-[4-(4,6-dimethyl-2-pyridyl)piperazin-1-yl]aniline (43.5 g, 98%).

Reference Examples 399 to 417

The compounds set out below were prepared in a manner analogous toReference Example 398 at a suitable pressure:

Reference Example Compound 3994-[4-(4,6-Dimethyl-2-pyridyl)piperazin-1-yl]-3-(3-morpholinopropoxymethyl)aniline 4003-Chloro-4-[4-(4,6-dimethyl-2-pyridyl)piperazin-1-yl]aniline 4013-(2-Dimethylaminoethoxymethyl)-4-[4-(4,6-dimethyl-2-pyridyl)piperazin-1-yl]aniline 4024-[4-(4,6-Dimethyl-2-pyridyl)piperazin-1-yl]-3-[3-(4-methylpiperazin-1-yl)propoxymethyl]aniline 4035-Amino-2-[4-(4,6-dimethyl-2-pyridyl)piperazin-1-yl]phenol 4042,3-Dihydrobenzofuran-4-amine 405 4-[4-(2-Pyridyl)piperazin-1-yl]aniline406 4-[4-(6-Methyl-2-pyridyl)piperazin-1-yl]aniline 4074-[4-(4-Methyl-2-pyridyl)piperazin-1-yl]aniline 4085-(4-Methylpiperazin-1-yl)naphthalen-1-amine 4094-[4-(4,6-Dimethyl-2-pyridyl)piperazin-1-yl]-3-methyl-aniline 4104-[4-[5-(Morpholinomethyl)-2-pyridyl]piperazin-1-yl]aniline 4113-Fluoro-4-(1-piperidyl)aniline 4123-Fluoro-4-(4-isobutylpiperazin-1-yl)aniline 4133-Fluoro-4-morpholino-aniline 414 5-Fluoro-naphthalen-1-amine 4154-(1-Piperidyl)aniline 416 4-Morpholinoaniline 4174-[4-(2-Methoxy-1-methyl-ethyl)piperazin-1-yl]aniline

Reference Example 418 5-Nitro-2-pyrrolidin-1-yl-pyridine

A mixture of 2-bromo-5-nitro pyridine (300 mg, 1.48 mmol) andpyrrolidine (313 mg, 4.41 mmol) in toluene (5 mL) was heated at 110° C.for 2 h. The reaction mixture was allowed to cool to ambienttemperature, poured onto ice-water, and the organic layer was separated.The aqueous layer was extracted with ethyl acetate (3×5 mL). Thecombined organic layers were washed with water, brine, dried overanhydrous sodium sulphate, filtered and concentrated in vacuo to afford5-nitro-2-pyrrolidin-1-yl-pyridine (250 mg, 88%) as a solid.

Reference Example 4192-Chloro-4-[4-(4,6-dimethyl-2-pyridyl)piperazin-1-yl]aniline

Stannous chloride dihydrate (2.6 g, 11.5 mmol) was added to a solutionof 1-(3-chloro-4-nitro-phenyl)-4-(4,6-dimethyl-pyridin-2-yl)-piperazine(800 mg, 2.31 mmol) in a mixture of ethyl acetate (20 mL) and ethanol (5mL). The reaction mixture was heated at reflux for 2 h, allowed to coolto ambient temperature and basified with triethylamine. The reactionmixture was filtered and the filtrate was concentrated in vacuo. Theresidue was purified by column chromatography over neutral alumina with10% ethyl acetate in petroleum ether as eluent to afford2-chloro-4-[4-(4,6-dimethyl-2-pyridyl)piperazin-1-yl]aniline (470 mg,64%) as a viscous light brown oil.

Reference Examples 420 to 428

The compounds set out below were prepared in a manner analogous toReference Example 419:

Example Compound 420 6-Pyrrolidin-1-yl-pyridin-3-amine 4211-Ethyl-4-fluoro-indol-5-amine 422 4-(4-Benzylpiperazin-1-yl)aniline 4234-Oxazol-2-ylaniline 424 3-Fluoro-4-oxazol-2-yl-aniline 4254-[4-(1,2-Dimethylpropyl)piperazin-1-yl]aniline 4261-[4-(4-Aminophenyl)piperazin-1-yl]-2-methyl-propan-1-one 4274-[4-[2-(2-Furyl)-1-methyl-ethyl]piperazin-1-yl]aniline 4284-[(5-Piperidylmethyl)oxazol-2-yl]aniline

Reference Example 429 5-Nitronaphthalen-1-amine

A 70° C. solution of sodium sulfide (3.17 g, 32.97 mmol) and sodiumbicarbonate in water (7 mL) was added dropwise to suspension of1,5-dinitro naphthalene (2.0 g, 9.16 mmol) in methanol (30 mL) at refluxand the resultant mixture was stirred for 5 min. The mixture was cooledto 0° C., quenched with ice and stirred for a further 10 min followed byacidification with concentrated hydrochloric acid. The resulting mixturewas stirred for 30 min then washed with ethyl acetate (2×50 mL). Theaqueous layer was basified with aqueous ammonia and extracted with ethylacetate (2×100 mL). The combined organic layers were washed with water(2×50 mL), brine (2×50 mL), dried over anhydrous sodium sulphate,filtrated and concentration in vacuo afforded of5-nitronaphthalen-1-amine (710 mg, 42%) as a brown solid.

Reference Example 430 5-Bromoisoquinoline

A solution of sodium nitrite (2.15 g, 31.21 mmol) in water (2 mL) wasadded to a solution of isoquinolin-5-ylamine (3.0 g, 20.80 mmol) inaqueous 46% hydrogen bromide (9.98 g, 124.84 mmol) at 0° C. The mixturewas stirred at 0° C. for 30 min then a solution of cuprous bromide (3.58g, 24.96 mmol) in aqueous 46% hydrogen bromide (9.98 g, 124.84 mmol) wasadded and the reaction was allowed to warm to ambient temperature andstirred for 2 h. The resulting mixture was basified with aqueousammonium and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulphate andconcentrated to afford the crude compound. Purification by columnchromatography over silica gel (100-200 mesh) with 20% ethyl acetate inpetroleum ether as eluent afforded 5-bromoisoquinoline (2.3 g, 53%) as apale yellow solid.

Reference Example 431 5-Bromo-8-nitro-isoquinoline

Potassium nitrate (1.17 g, 11.59 mmol) was added portion-wise to asolution of 5-bromo-isoquinoline (2.0 g, 9.66 mmol) in concentratedsulphuric acid (10 mL) and stirred at ambient temperature for 1 h. Thereaction mixture was quenched with water and basified with aqueousammonia. The aqueous layer was washed with water, brine, dried overanhydrous sodium sulphate and concentrated in vacuo to afford5-bromo-8-nitro-isoquinoline (2.0 g, 82%) as a yellow solid.

Reference Example 432 3-Phenylfuran

Furan-3-boronic acid (1.0 g, 8.93 mmol), bromo benzene (1.26 g, 8.04mmol) and sodium carbonate (1.89 g, 17.86 mmol) were dissolved in amixture of toluene (15 mL) and methanol (5 mL) and purged with argon for15 min. Tetrakis palladium (0) (20 mg) was added and the mixture againdegassed for 15 min. The reaction was heated at 80° C. for 4 h and theresultant solids which formed were filtered and the filtrate wasconcentrated in vacuo to give a crude residue. Purification by flashchromatography over silica gel (100-200 mesh) using 2% ethylacetate/petroleum ether as eluent afforded 3-phenylfuran (0.9 g, 70%).

Reference Example 433 2,5-Dimethoxy-3-phenyl-2,5-dihydrofuran

Bromine (0.83 g, 5.31 mmol) dissolved in methanol (5 mL) was added dropwise to a solution of 3-phenylfuran (0.85 g, 5.90 mmol) in methanol (5mL) and diethyl ether (3 mL) at −40° C. The resultant mixture wasallowed to warm to −25° C. and stirred for a further 2 h. The reactionthe mixture was quenched with ice cold water and extracted with diethylether. The combined organic extracts were washed with saturatedbicarbonate solution, dried over anhydrous sodium sulfate andconcentrated in vacuo to give the crude compound. Purification by flashchromatography over silica gel (100-200 mesh) with 2% ethylacetate/petroleum ether as eluent afforded2,5-dimethoxy-3-phenyl-2,5-dihydrofuran (0.65 g, 54%).

Reference Example 434 Isoquinolin-8-amine

A suspension of 5-bromo-8-nitro-isoquinoline (2.0 g, 7.93 mmol),triethylamine (1.2 g, 11.90 mmol) and Pd/C (10%; 200 mg) indimethylformamide (10 mL) was hydrogenated at atmospheric pressure for 2h. The reaction mixture was filtered through Celite and washed withethyl acetate. The filtrate was concentrated in vacuo to affordisoquinolin-8-amine (700 mg, 66%) as a pale yellow solid.

Reference Examples 435 and 436

The compounds set out below were prepared in a manner analogous toReference Example 434:

Example Compound 435 2,5-Dimethoxy-3-phenyl-tetrahydrofuran 4363-Fluoro-4-[4-(2-pyridyl)piperazin-1-yl]aniline

Reference Example 437 Naphthalen-2-amine

Polyphosphoric acid (7.5 g) was added to a mixture of 2-naphthoic acid(600 mg, 3.48 mmol) and hydroxylamine hydrochloride (254 mg, 3.66 mmol)at room temperature and heated slowly to 160° C. The reaction mixturewas stirred for 90 min and then allowed to cool to ambient temperatureand quenched with crushed ice (50 g). The resultant solid was filteredand washed with water (2×20 mL). The combined filtrate and washings werebasified with 10% potassium hydroxide solution (100 mL). Theprecipitated solid was filtered, washed with water (2×25 mL), petroleumether (2×20 mL), diethyl ether (2×20 mL) and dried in vacuo to affordnaphthalen-2-amine (165 mg, 34%) as a light pink solid.

Reference Example 438 2-Fluoro-4-[4-(2-pyridyl)piperazin-1-yl]aniline

2-Fluoro-4-iodoaniline (750 mg, 3.16 mmol) was added to a suspension of2-pyridyl-piperazine (568 mg, 3.48 mmol), 8-hydroxyquinoline (68 mg,0.47 mmol) and potassium carbonate (660 mg, 4.74 mmol) indimethylsulfoxide (5 mL) under an inert atmosphere. Cuprous iodide (94mg, 0.47 mmol) was added and the reaction mixture was heated at 140-145°C. for 16 h. The reaction mixture was allowed to cool to ambienttemperature and poured into a mixture of ammonium hydroxide, ethylacetate and charcoal and stirred for 30 min. The organic layer wasseparated and the aqueous layer extracted with ethyl acetate (2×75 mL).The combined organic layers were washed with brine (100 mL), dried oversodium sulphate and concentrated to dryness in vacuo. The crude productwas purified by column chromatography with silica gel (100-200 mesh)using 13% ethyl acetate in petroleum ether as eluent to afford2-fluoro-4-[4-(2-pyridyl)piperazin-1-yl]aniline (220 mg, 26%) as anorange semi-solid.

Examples 439 to 444

The compounds set out below were prepared in a manner analogous toReference Example 438:

Reference Example Compound 439 2-Fluoro-4-morpholino-aniline 4402-Fluoro-4-(4-isobutylpiperazin-1-yl)aniline 4412-Fluoro-4-(1-piperidyl)aniline 4422-Fluoro-4-[4-(2-methylallyl)piperazin-1-yl]aniline 4434-[4-(2,2-Dimethylpropyl)piperazin-1-yl]-2-fluoro-aniline 4444-[4-(4,6-Dimethyl-2-pyridyl)piperazin-1-yl]-2-fluoro-aniline

Reference Example 445 3-Fluoro-4-nitro-benzoic acid

2-Fluoro-4-methyl-1-nitro-benzene (1.0 g, 12.9 mmol) was addedportion-wise to a suspension of potassium dichromate (5.04 g, 17.16mmol) in glacial acetic acid (8 mL) follow by concentrated sulfuric acid(3.6 mL). The reaction mixture was heated to 120° C. for 2 h and thenallowed to cool to ambient temperature. The reaction was quenched withcrushed ice and extracted with ethyl acetate. The organic layer waswashed with brine, dried over anhydrous sodium sulfate and concentratedin vacuo to afford 3-fluoro-4-nitro-benzoic acid (1.9 g, 83%) as a whitesolid.

Reference Example 446 3-Fluoro-4-nitro-benzoyl chloride

A stirred solution of 3-fluoro-4-nitro-benzoic acid (1.65 g, 8.91 mmol)in thionyl chloride (10 mL) was heated at reflux for 2 h. Excess thionylchloride was evaporated in vacuo and the residue azeotroped with tolueneto afford 3-fluoro-4-nitro-benzoyl chloride (1.7 g, 99%) as a brown oil.

Reference Example 447

The compound set out below was prepared in a manner analogous toReference Example 446:

Reference Example Compound 447 2-Fluoro-4-nitro-benzoyl chloride

Reference Example 448 N-(2,2-Dimethoxyethyl)-3-fluoro-4-nitro-benzamide

To a cooled solution of amino acetaldehyde dimethyl acetal (0.91 mL,8.30 mmol) in dry tetrahydrofuran (15 mL) was added sodium bicarbonate(769 mg, 9.16 mmol) and then a solution of 3-fluoro-4-nitro-benzoylchloride (1.7 g, 8.30 mmol) in dry tetrahydrofuran (15 mL) was addeddropwise at 0° C. over a period of 30 min. The reaction mixture wasstirred overnight at ambient temperature, the solvent was removed invacuo, and the residue was diluted with water and extracted with ethylacetate. The organic layer was washed with water, brine, dried overanhydrous sodium sulfate and concentrated to yieldN-(2,2-dimethoxyethyl)-3-fluoro-4-nitro-benzamide (2.0 g, 90%) as abrown liquid.

Reference Example 449 to 450

The compounds set out below were prepared in a manner analogous toReference Example 448:

Reference Example Compound 449 N-(2,2-Dimethoxyethyl)-4-nitro-benzamide450 N-(2,2-Dimethoxyethyl)-2-fluoro-4-nitro-benzamide

Reference Example 451 2-(3-Fluoro-4-nitrophenyl)oxazole

Phosphorous pentoxide (4.14 g, 29.41 mmol) was added portion-wise to asolution of N-(2,2-dimethoxyethyl)-3-fluoro-4-nitro-benzamide (2.0 g,7.35 mmol) in methane sulphonic acid (3 mL) at 0° C. over a period of 30min. The mixture was heated to 145° C. for 5 h. The reaction mixture wasallowed to cool to ambient temperature and quenched with crushed ice andthen extracted with ethyl acetate. The combined organic layers werewashed with water, brine, dried over anhydrous sodium sulfate andconcentrated to afford the crude residue. Purification by flashchromatography with silica (60-120 mesh) using 15% ethylacetate-petroleum ether as eluent to afforded2-(3-fluoro-4-nitrophenyl)oxazole (500 mg, 33%) as a white solid.

Examples 452 to 453

The compounds set out below were prepared in a manner analogous toReference Example 451:

Reference Example Compound 452 2-(4-Nitrophenyl)oxazole 4532-(2-Fluoro-4-nitrophenyl)oxazole

Reference Example 454 1-Ethyl-4-fluoro-5-nitro-indole

2,3-Dichloro-5,6-dicyanohydroquinone (1.02 g, 4.50 mmol) was added tothe solution of 4-fluoro-5-nitro-2,3-dihydro-indole (0.47 g, 2.25 mmol)in benzene (30 mL) and the mixture was refluxed for 7 h. The solvent wasremoved in vacuo and the residue partitioned between ethyl acetate (100mL) and water (100 mL). The organic phase was washed with water (3×10mL), brine (3×10 mL), dried over anhydrous sodium sulphate andconcentration in vacuo afforded the crude product. Purification bycolumn chromatography over neutral alumina using 5% ethyl acetate inhexane as eluent afforded 1-ethyl-4-fluoro-5-nitro-indole (0.33 g, 72%)as yellow solid.

Reference Example 455 1-ethyl-4-fluoro-5-nitro-indoline

Anhydrous potassium carbonate (0.83 g, 6 mmol) was added to a solutionof 4-fluoro-5-nitro-indoline (0.54 g, 3 mmol) in acetone (20 mL). Themixture was stirred at 60° C. for 10 min and ethyl bromide (0.33 mL,4.50 mmol) added dropwise and the mixture was refluxed for a further 12h. The mixture was concentrated in vacuo and the residue partitionedbetween ethyl acetate (50 mL) and water (50 mL). The organic layer wasseparated and the aqueous layer extracted with ethyl acetate (5×10 mL).The combined organic layers were washed with water (3×10 mL), brine(3×10 mL) and then dried over anhydrous sodium sulphate. Concentrationof the organic layer afforded the crude product which was purified bycolumn chromatography over silica gel neutral alumina mesh using 5-8%ethyl acetate in hexane as eluent to afford1-ethyl-4-fluoro-5-nitro-indoline (0.47 g, 75%) as a yellow solid.

Reference Example 456 4-Fluoro-5-nitro-indoline

A mixture of 1-(4-fluoro-5-nitro-indolin-1-yl)ethanone (0.56 g, 2.51mmol) and concentrated hydrochloric acid (10 mL) was refluxed for 16 h.The reaction mixture was cooled to ambient temperature and partitionedbetween chlorofolin (100 mL) and water (100 mL). The organic layer wasseparated and the aqueous layer extracted with chloroform (5×30 mL). Thecombined organic layers were washed with water (3×20 mL), brine (3×20mL) and dried over anhydrous sodium sulphate. Concentration in vacuoafforded 4-fluoro-5-nitro-indoline (0.35 g, 76%) as a yellow solid.

Reference Example 457 1-(4-Fluoro-5-nitro-indolin-1-yl)ethanone

Fuming nitric acid (0.22 mL) was added dropwise to a solution of1-(4-fluoro-indolin-1-yl)ethanone (1 g, 5.58 mmol) in concentratedsulfuric acid (10 mL) at −15° C. to 0° C. The reaction mixture wasstirred at 0° C. for 2 h and then the resulting mixture was basifiedwith sodium bicarbonate solution (100 mL). The reaction mixture waspartitioned between chloroform (100 mL) and water (100 mL). The organiclayer was separated and the aqueous layer was extracted with chloroform(5×30 mL). The combined organic layers were washed with water (3×20 mL),brine (3×20 mL), dried over anhydrous sodium sulphate and concentratedin vacuo to give the crude product. Purification by columnchromatography over neutral alumina using 10-12% ethyl acetate in hexaneas eluent afforded 1-(4-fluoro-5-nitro-indolin-1-yl)ethanone (0.56 g,45%) as a yellow solid.

Reference Example 458 1-(4-Fluoro-indolin-1-yl)ethanone

A mixture of 4-fluoro-indoline (1 g, 7.30 mmol) and acetic anhydride (10mL) was stirred at ambient temperature for 1 h. The resulting mixturewas partitioned between ethyl acetate (100 mL) and water (100 mL). Theorganic layer was separated and the aqueous layer was extracted withethyl acetate (5×30 mL). The combined organic layers were washed withwater (3×20 mL), sodium bicarbonate solution (3×20 mL), brine (3×20 mL),dried over anhydrous sodium sulphate and concentrated in vacuo to afford1-(4-fluoro-indolin-1-yl)ethanone (1 g, 77%) as a white solid.

Reference Example 459 4-Fluoroindoline

Sodium cyanoborohydride (1.86 g, 29.62 mmol) was added portion wise to asolution of 4-fluoro-1H-indole (2 g, 14.81 mmol) in acetic acid (20 mL)at 0° C. and stirred at ambient temperature for 2 h. The resultingmixture was concentrated in vacuo and partitioned between ethyl acetate(100 mL) and water (100 mL). The organic layer was separated and theaqueous layer was extracted with ethyl acetate (5×30 mL). The combinedorganic layers were then washed with water (5×20 mL), sodium bicarbonatesolution (3×30 mL), brine (3×20 mL), dried over anhydrous sodiumsulphate and concentrated in vacuo to give the crude product.Purification by column chromatography over neutral alumina using 5%ethyl acetate in hexane as eluent to afforded 4-fluoroindoline (1 g,45%) as a brown liquid.

Reference Example 460 4-Fluoro-1H-indole

Raney Nickel (500 mg) was added to a suspension of1-[2-(2-fluoro-6-nitro-phenyl)vinyl]pyrrolidine (6 g, 25.42 mmol) inmethanol (50 mL) and hydrogenated under atmospheric pressure at ambienttemperature for 20 h. The mixture was filtered through a pad of Celiteand the filtrate was concentrated in vacuo to afford 4-fluoro-1H-indole(2.05 g, 60%) as a brown liquid.

Reference Example 461 1-[2-(2-Fluoro-6-nitro-phenyl)vinyl]pyrrolidine

Pyrrolidine (0.26 mL, 3.22 mmol) was added to a solution of2-fluoro-6-nitrotoluene (5 g, 32.23 mmol) in N,N-dimethyl formamidedimethyl acetal (50 mL) and refluxed for 48 h. The resulting mixture wascooled to ambient temperature and partitioned between ethyl acetate (150mL) and water (150 mL). The organic layer was separated and the aqueouslayer extracted with ethyl acetate (5×30 mL). The combined organiclayers were washed with water (3×30 mL), brine (3×20 mL), dried overanhydrous sodium sulphate and concentrated in vacuo to give1-[2-(2-fluoro-6-nitro-phenyl)vinyl]pyrrolidine (6.08 g, 80%) as brownliquid.

Reference Example 462 2-Fluoro-4-oxazol-2-yl-aniline

A stirred solution of 2-(3-fluoro-4-nitro-phenyl)oxazole (500 mg, 2.40mmol) in methanol (10 mL) was added to stannous chloride (2.7 g, 12.01mmol) under nitrogen atmosphere and stirred for 16 h. The reactionmixture was diluted with water and filtered through Celite. The filtratewas basified with bicarbonate solution and extracted with ethyl acetate.The organic layer was washed with water, brine, dried over anhydroussodium sulfate and concentrated in vacuo to afford2-fluoro-4-oxazol-2-yl aniline (350 mg, 83%) as a yellow colour solid.

Reference Example 463 1-(Chloromethoxy)butane

Hydrogen chloride was continuously passed through a suspension ofn-butanol (10 g, 135.13 mmol) and paraformaldehyde (4.06 g, 135.33 mmol)until the mixture appeared transparent with two separate layers. Theupper layer was separated and fractionally distilled to afford1-Chloromethoxy-butane (8 g, 48%).

Reference Example 464 4-Methoxybutyl-4-methylbenzenesulfonate

Triethylamine (2.91 g, 28.86 mmol) was added to the stirred solution of4-methoxy-1-butanol (1.00 g, 9.62 mmol) in dichloromethane (15 mL) at 0°C. and stirred for 15 min. p-Toluene sulfonyl chloride (1.83 g, 9.62mmol) was added and the mixture was warmed to ambient temperature andstirred for 2 h. The reaction mixture was quenched with ice-water andthe organic layer was separated. The aqueous layer was extracted withdichloromethane (3×5 mL) and the combined organic layers were washedwith saturated sodium bicarbonate, water, and brine; dried overanhydrous sodium sulphate and concentrated in vacuo. The crude productwas purified by column chromatography over silica gel (60-120 mesh) with0% to 20% ethyl acetate in petroleum ether as eluent to afford4-methoxybutyl-4-methylbenzenesulfonate (800 mg, 32%) as a liquid.

Reference Example 465 4-(Bromomethyl)-2-methyl-oxazole

Carbon tetrabromide (1.58 g 4.77 mmol) and triphenylphosphine (1.25 g4.77 mmol) were added to a solution of (2-methyloxazol-4-yl)methanol(450 mg 3.98 mmol) in dry acetonitrile (8 mL) and the mixture wasstirred for 12 h at ambient temperature. The volatiles were removed invacuo to afford the crude product which was used without furtherpurification.

Reference Example 466 (2-Methyloxazol-4-yl)methanol

1M Diisobutyl aluminum hydride (23.23 mL; 23.23 mmol) was added to asolution of methyl 2-methyloxazol-4-carboxylate (1.1 g, 7.80 mmol) indry tetrahydrofuran (25 mL) at −60° C. The resulting mixture was allowedto warm to ambient temperature and was stirred for 3 h. Saturatedaqueous ammonium chloride was added and the resultant suspension wasfiltered and the organic layer separated. The aqueous layer wasextracted with ethyl acetate (2×25 mL) and the combined organic layerswashed with brine, dried over anhydrous sodium sulfate and concentratedin vacuo to afford (2-methyloxazol-4-yl)methanol (450 mg, 51%) as asemi-solid.

Reference Example 467 Methyl 2-methyloxazol-4-carboxylate

Hexamethylenetetramine (11.7 g, 5.00 mmol) and1,8-diazabicyclo(5,4,0)undec-7-ene were added to a stirred suspension ofcopper bromide (18.7 g, 83.85 mmol) in dichloromethane (50 mL) at 0° C.and purged with argon gas for 20 min. To the mixture was added methyl2-methyl-4,5-dihydrooxazole-4-carboxylate (3 g, 20.97 mmol) at 0° C. Themixture was allowed to warm to ambient temperature and stirred for afurther 12 h. The solvent was removed in vacuo and the resulting residuepartitioned between ethyl acetate and 1:1 saturated aqueous ammoniumchloride and ammonium hydroxide. The organic layer was separated and theaqueous layer extracted with ethyl acetate (2×20 mL). The combinedorganic layers were washed with 1:1 saturated aqueous ammonium chlorideand ammonium hydroxide, 10% aqueous citric acid, saturated sodiumbicarbonate solution, brine, dried over anhydrous sodium sulfate andconcentrated in vacuo to afford methyl 2-methyloxazol-4-carboxylate (1.1g, 34%) as a solid.

Reference Example 468 Methyl 2-methyl-4,5-dihydrooxazole-4-carboxylate

Triethylamine (5.86 g, 58.01 mmol) was added to a suspension of L-serinemethyl hydrochloride (4.5 g, 29.03 mmol) and ethylacetimidatehydrochloride (4.3 g, 34.95 mmol) in dichloromethane (40 mL) at 0° C.over a period of 20 min. The mixture was then stirred at ambienttemperature for 18 h. The suspension was filtered and washed withdiethyl ether. The solid which precipitated from the filtrate was againfiltered and washed with diethyl ether. The resulting filtrate was driedover anhydrous sodium sulfate and concentrated in vacuo to afford methyl2-methyl-4,5-dihydrooxazole-4-carboxylate (3 g, 72%) as a liquid.

Example 12-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide

A solution of (1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-oxo-acetyl chloride(46 g, 0.176 mol) in dry dichloromethane (300 mL) was added to asolution of 4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylamine(40 g, 0.140 mol) and triethylamine (14.2 g, 0.140 mol) in drydichloromethane (300 mL) over 15 min. After stirring for 1 h thereaction mixture was quenched into water (200 mL) and the organic phaseseparated. The aqueous layer was extracted with dichloromethane (2×50mL) and the combined organic layers were washed successively with water(2×200 mL), brine (2×100 mL), dried over anhydrous sodium sulfate andconcentrated to give a solid. This was dissolved in acetone (580 mL) andsilica gel was added (72.5 g, 100-200 mesh). The mixture was stirred atroom temperature for 1 h, filtered and the solids washed with acetone(75 mL). The silica treatment was repeated a second time. The filtratewas concentrated to ˜300 mL (˜4 vols), activated carbon (8 g) was addedand heated at reflux for 15 min. The mixture was cooled to 45-50° C. andfiltered over celite, washing with acetone (75 mL). The solution wasagain concentrated to ˜300 mL and petroleum ether (725 mL, 10 vols) wasadded, slowly, at reflux. The resulting suspension was cooled to roomtemperature, stirred for 15 min, then cooled to 0° C. and stirred for 1h. The solid was filtered off, washed with petroleum ether (150 mL) anddried under vacuum to afford2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide(53.5 g, 74%) as a yellow solid.

The compounds set out below were prepared in a manner analogous toExample 1:

Example Compound  2N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(1-phenyl-1H-pyrrol-2-yl)-acetamide  3N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-1-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide  4N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-1H-pyrrol-2-yl)-2-oxo-acetamide  5N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(2-methyl-7-phenyl-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-6-yl)-2-oxo-acetamide 6 N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(2-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl)-acetamide  7N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(7-phenyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-acetamide  8N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-isopropyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide  9N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide  102-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-3-(3-morpholin-4-yl-propoxymethyl)-phenyl]-2-oxo-acetamide  11N-{3-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide  12N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(3-furan-2-yl-1,5-dimethyl-1H-pyrrol-2-yl)-2-oxo-acetamide  13N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1,5-dimethyl-3-thiophen-2-yl-1H-pyrrol-2-yl)-2-oxo-acetamide  14N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(3-isopropyl-1,5-dimethyl-1H-pyrrol-2-yl)-2-oxo-acetamide  15N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1,5-dimethyl-3-(tetrahydro-pyran-4-yl)-1H-pyrrol-2-yl]-2-oxo-acetamide  162-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-naphthalen-1-yl-2-oxo-acetamide 17N-{3-(2-Dimethylamino-ethoxymethyl)-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide  182-(1,4-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide  192-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-3-[3-(4-methyl-piperazin-1-yl)-propoxymethyl]-phenyl}-2-oxo-acetamide  20N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-isopropyl-1-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide  21N-{2-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide  222-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-3-hydroxy-phenyl}-2-oxo-acetamide  23N-(2,3-Dihydro-benzofuran-4-yl)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide  24N-{3-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide 25 N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[3-isopropyl-1-(2-methoxy-ethyl)-5-methyl-1H-pyrrol-2-yl]-2-oxo-acetamide 26N-{2-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide 27 N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-ethoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide  28N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(3-methoxy-propyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide  292-[1-(2-Methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-N-quinolin-5-yl-acetamide  30N-Isoquinolin-5-yl-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide  312-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-quinolin-8-yl-acetamide 322-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-quinolin-5-yl-acetamide 332-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-pyridin-4-yl-acetamide 34 N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-ethyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide  35N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-3-phenyl-1-propyl-1H-pyrrol-2-yl)-2-oxo-acetamide  362-(1-Butyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide  372-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-quinolin-3-yl-acetamide 38 2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-[4-(4-pyridin-2-yl-piperazin-1-yl)-phenyl]-acetamide  392-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(6-methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide  402-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4-methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide  41aN-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(2-phenyl-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepin-3-yl)-acetamide 41bN-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(1-phenyl-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepin-3-yl)-acetamide  42N-Isoquinolin-8-yl-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide  432-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-isoquinolin-8-yl-2-oxo-acetamide  442-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-naphthalen-2-yl-2-oxo-acetamide  45N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide  46N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-methyl-4-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide  47N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide  482-(1-Benzyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide  492-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[5-(4-methyl-piperazin-1-yl)-naphthalen-1-yl]-2-oxo-acetamide  50N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide  512-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-3-methyl-phenyl}-2-oxo-acetamide  52(2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-5-methyl-3-phenyl-pyrrol-1-yl)-acetic acid methylester  53N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-ethyl-1-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide  54N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[5-ethyl-1-(2-methoxy-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide  552-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-5-methyl-3-phenyl-pyrrole-1-carboxylic acid ethylester  56 2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-5-methyl-3-phenyl-pyrrole-1-carboxylic acid methylester  572-[3-(2-Chloro-phenyl)-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide  582-[4-(2-Chloro-phenyl)-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide  592-[3-(4-Chloro-phenyl)-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide  602-[1-(2-Methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-N-phenyl-1-acetamide  61(2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-pyrrol-1-yl)-acetic acid methyl ester  62N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-methoxymethyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide  63N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-methoxymethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide  652-[1-(2-Acetylamino-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide 66 N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-hydroxy-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide  67N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-3-thiophen-2-yl-1H-pyrrol-2-yl]-2-oxo-acetamide  68N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[3-isobutyl-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-2-oxo-acetamide  69(2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-5-methyl-3-phenyl-pyrrol-1-yl)-acetic acid ethylester  702-[3-(3-Chloro-phenyl)-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide  712-[4-(3-Chloro-phenyl)-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide  73(2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-3-phenyl-pyrrol-1-yl)-acetic acid ethyl ester  74(2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-3-phenylpyrrol-1-yl)-acetic acid methyl ester  77(2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-5-methyl-3-phenyl-pyrrol-1-yl)-acetic acid isopropylester  78N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperizin-1-yl]-phenyl}-2-[5-isopropyl-1-(2-methoxy-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo- acetamide 79 2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-quinolin-5-yl-acetamide  80N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[3-(2-methoxy-ethyl)-5-methyl-1-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide  812-[1-(2-Methoxy-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-N-phenyl-acetamide  822-[1-(2-Methoxy-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-N-propyl-acetamide  83N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[3-isopropyl-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-2-oxo-acetamide  842-[1-(2-Dimethylamino-ethyl)-3-phenyl-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide  852-[1-(2-Dimethylamino-ethyl)-4-phenyl-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide  862-[1-(2-Dimethylamino-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide  87 (2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-3-thiophen-2-yl-pyrrol-1-yl)-acetic acid methyl ester 88 (2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-[3-isopropyl-pyrrol-1-yl)-acetic acid methyl ester 89 (2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-3-isobutyl-pyrrol-1-yl)-acetic acid methyl ester  90N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(4-fluoro-1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide  91N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-3-phenyl-1-pyridin-2-ylmethyl-1H-pyrrol-2-yl)-2-oxo- acetamide 92N-{2-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide  93N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-3-phenyl-1-pyridin-3-ylmethyl-1H-pyrrol-2-yl)-2-oxo- acetamide 94 N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[4-fluoro-1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide  952-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[2-fluoro-4-(4-pyridin-2-yl-piperazin-1-yl)-phenyl]-2-oxo-acetamide  96N-[2-Fluoro-4-(4-pyridin-2-yl-piperazin-1-yl)-phenyl]-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide  97N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-isopropoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide  98(2-{2-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-5-methyl-3-phenyl-pyrrol-1-yl)-acetic acid methylester  992-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-(6-pyrrolidin-1-yl-pyridin-3-yl)-acetamide 1002-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[2-fluoro-4-oxazol-2-yl-phenyl)-2-oxo-acetamide 1012-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(2-fluoro-4-morpholin-4-yl-phenyl)-2-oxo-acetamide 102N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-3-phenyl-1-pyridin-4-ylmethyl-1H-pyrrol-2-yl)-2-oxo- acetamide103 2-[1-(2-Methoxy-ethyl)-5-methyl-3-pheny-1H-pyrrol-2-yl]-N-{4-[4-(5-morpholin-4-ylmethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide 1042-[3-Cyclobutyl-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperizin-1-yl]-phenyl}-2-oxo-acetamide 1052-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[2-fluoro-4-(4-isobutyl-piperazin-1-yl)-phenyl]-2-oxo-acetamide 1062-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(2-fluoro-4-piperidin-1-yl-phenyl)-2-oxo-acetamide 107(3-Cyclobutyl-2-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-pyrrol-1-yl)-acetic acid methyl ester 1082-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{2-fluoro-4-[4-(2-methyl-allyl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide 109N-{2-Fluoro-4-[4-(2-methyl-allyl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide 110N-[2-Fluoro-4-(4-isobutyl-piperazin-1-yl)-phenyl]-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide 111(2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-2-fluoro-phenylaminooxalyl}-5-methyl-3-phenyl-pyrrol-1-yl)-acetic acid methylester 1122-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(2,2-dimethyl-propyl)-piperazin-1-yl]-2-fluoro-phenyl}-2-oxo-acetamide 113N-{4-[4-(2,2-Dimethyl-propyl)-piperazin-1-yl]-2-fluoro-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide 114N-(2-Fluoro-4-piperidin-1-yl-phenyl)-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide 1152-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-fluoro-4-piperidin-1-yl-phenyl)-2-oxo-acetamide 1162-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[3-fluoro-4-(4-pyridin-2-yl-piperazin-1-yl)-phenyl]-2-oxo-acetamide 117N-(2-Fluoro-4-morpholin-4-yl-phenyl)-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide 1182-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[3-fluoro-4-(4-isobutyl-piperazin-1-yl)-phenyl]-2-oxo-acetamide 119N-(3-Fluoro-4-piperdin-1-yl-phenyl)-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide 1202-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(5-morpholin-4-ylmethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide 1212-[1-(2-Methoxy-ethyl)-4-phenyl-1H-pyrrol-2-yl]-2-oxo-N-propyl-acetamide 122 (2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-4-phenyl-pyrrol-1-yl)-acetic acid methyl ester 123N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-2-fluoro-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide 124N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperizin-1-yl]-phenyl}-2-[1-methyl-3-phenyl-5-propyl-1H-pyrrol-2-yl)-2-oxo-acetamide 125N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-ethyl-1-methoxymethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide 1272-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(5-fluoro-naphthalen-1-yl)-2-oxo-acetamide 132N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-ethoxymethyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide 133N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[5-methyl-1-(2-methylsulfanyl-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide 134N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[5-methyl-1-(2-phenoxy-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide 1352-(1-Butoxymethyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide 136N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(3-ethoxy-propyl)-5-methy-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide 138N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethoxymethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo- acetamide139 N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-3-phenyl-1-propoxymethyl-1H-pyrrol-2-yl)-2-oxo-acetamide 140N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[5-methyl-3-phenyl-1-(2-propoxy-ethyl)-1H-pyrrol-2-yl]-2-oxo-acetamide 141N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(4-methoxy-but-2-enyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo- acetamide142 N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(4-methoxy-butyl)-5-methy-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide 1432-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-(4-piperidin-1-yl-phenyl)-acetamide 1482-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[3-fluoro-4-oxazole-2-yl-phenyl)-2-oxo-acetamide 1542-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-morpholin-4-yl-phenyl)-2-oxo-acetamide

Example 126N-(3-Fluoro-4-morpholin-4-yl-phenyl)-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide

Oxalyl chloride (0.19 g, 1.53 mmol) was added to a solution of1-(2-methoxy-ethyl)-2-methyl-4-phenyl-1H-pyrrole (0.30 g, 1.39 mmol) inchloroform (5 mL) at 0° C. and slowly warmed the ambient temperature toRT over 30 min. Completion of reaction and removal of excess oxalylchloride in vacuo afforded the intermediate acid chloride,[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-oxo-acetylchloride which was taken in chloroform (5 mL). This was then added to asolution of 3-fluoro-4-morpholin-4-yl-phenylamine (0.19 g, 0.97 mmol) inchloroform (5 mL) with triethyl amine (0.28 g, 2.78 mmol). The reactionwas stirred for 30 min at ambient temperature and then diluted withwater and extracted into chloroform. Combined organic extracts werewashed with saturated bicarbonate solution, dried over anhydrous sodiumsulfate and stirred over neutral alumina for 10 min. The mixture wasfiltered and concentrated in vacuo to affordN-(3-fluoro-4-morpholin-4-yl-phenyl)-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide(0.26 g, 40%) as pale yellow solid.

The compounds set out below were prepared in a manner analogous toExample 126:

Example Compound 1282-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(1-ethyl-4-fluoro-1H-indol-5-yl)-2-oxo-acetamide 129N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[5-(2-methoxy-ethyl)-1-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide 137N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-1-methylsulfanylmethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo- acetamide144 N-[4-(4-Benzyl-piperazin-1-yl)-phenyl]-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide 1452-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[4-(4-isobutyryl-piperazin-1-yl)-phenyl]-2-oxo-acetamide 146N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[5-methyl-1-(2-methyl-oxazol-4-ylmethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide 1472-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-oxazol-2-yl-phenyl)-2-oxo-acetamide 1492-[1-(2-Methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-N-(4-oxazol-2-yl-phenyl)-2-oxo-acetamide 1502-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(1,2-dimethyl-propyl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide 1512-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(2-methoxy-1-methyl-ethyl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide 1522-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(2-furan-2-yl-1-methyl-ethyl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide 1532-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-[4-(5-piperdin-1-ylmethyl-oxazol-2-yl)-phenyl]-acetamide

Example 64N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-hydroxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide

Lithium hydroxide monohydrate (30 mg, 0.70 mmol) was added to asuspension of acetic acid2-(2-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-5-methyl-3-phenyl-pyrrol-1-yl)-ethylester (340 mg, 0.59 mmol) in methanol (10 mL) at room temperature andstirred for 60 min. The solvent was evaporated in vacuo and theresulting residue dissolved in water (20 mL). The solution was acidifiedwith 1N acetic acid to adjust the pH to ˜6 to 7 and the aqueous layerwas extracted with ethyl acetate (2×25 mL). The combined organic layerwas washed with water (2×30 mL), brine (2×30 mL), dried over anhydroussodium sulphate and concentrated in vacuo to yield the crude compound.Purification by preparative TLC using 2.5% of methanol in chloroform aseluent affordedN-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-hydroxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide(230 mg, 73%) as an orange solid.

Example 72N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-3-thiophen-3-yl-1H-pyrrol-2-yl]-2-oxo-acetamide

Diisopropylethylamine (0.40 mL, 2.17 mmol),(2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) (0.28 mg, 0.72 mmol) was added to a solution of[1-(2-methoxy-ethyl)-3-thiophen-3-yl-1H-pyrrol-2-yl]-oxo-acetic acid(200 mg, 0.72 mmol) in dry dichloromethane at room temperature and thereaction mixture stirred for 1 h.4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylamine (160 mg,0.56 mmol) was added and the mixture was then heated in a sealed tube at90° C. for 18 h. The reaction mixture was cooled to room temperature,washed with water and brine. The organic layer was dried over anhydroussodium sulfate and evaporated under reduced pressure to give crudecompound which was purified by preparative HPLC to affordN-{4-[4-(4,6-dimethyl-pyridin-2-yl)piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-3-thiophen-3-yl-1H-pyrrol-2-yl]-2-oxo-acetamide(80 mg, 20%) as a solid.

The compounds set out below were prepared in a manner analogous toExample 72:

Example Compound 130N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methoxymethyl-1-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide 1312-(1,5-Bis-methoxymethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazine-1-yl]-phenyl}-2-oxo-acetamide

Example 752-(1-Carbamoylmethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide

(2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-3-phenyl-pyrrol-1-yl)aceticethyl acid ester (100 mg, 0.17 mmol) and methanolic ammonia (5 mL) wereheated at 60° C. in a sealed tube for 2 h. On completion of the reactionthe volatiles were removed in vacuo to give the crude compound, whichwas purified by preparative HPLC to afford2-(1-carbamoylmethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide(70 mg, 74%) as a yellow powder.

The compound set out below was prepared in a manner analogous to Example75:

Example Compound 76 N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-methylcarbamoylmethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide

MS Example NMR Data Spectrum 1 ¹H NMR (400 MHz, CDCl₃) δ 8.20 (s, 1H),7.31-7.28 (m, 508 (M + H) 2H), 7.27-7.21 (m, 4H), 7.09 (d, 2H), 6.84 (d,2H), 6.38 (s, 1H), 6.31 (s, 1H), 6.13 (s, 1H), 3.81 (s, 3H), 3.65 (t,4H), 3.22 (t, 4H), 2.37 (s, 3H), 2.32 (s, 3H), 2.23 (s, 3H) 2 ¹H NMR(400 MHz, CDCl₃) δ 9.00 (s, 1H), 8.23 (dd, 1H), 480 (M + H) 7.53 (d,2H), 7.47-7.45 (m, 3H), 7.31-7.29 (dd, 2H), 7.16 (t, 1H), 6.95 (d, 2H),6.44 (s, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.65 (t, 4H), 3.24 (t, 4H),2.38 (s, 3H), 2.24 (s, 3H) 3 ¹H NMR (400 MHz, CDCl₃) δ 9.01 (s, 1H),8.21 (d, 1H), 494 (M + H) 7.53-7.50 (m, 5H), 7.23-7.21 (m, 2H), 6.94 (d,2H), 6.38 (s, 1H), 6.31 (s, 1H), 6.23 (d, 1H), 3.69 (s, 4H), 3.26 (s,4H), 2.38 (s, 3H), 2.23 (s, 3H), 2.09 (s, 3H) 4 ¹H NMR (400 MHz, CDCl₃):δ 11.4 (broad s, 1H), 418 (M + H) 9.35 (broad s, 1H), 7.60 (d, 2H), 7.33(broad s, 1H), 6.98 (d, 2H), 6.39 (s, 1H), 6.32 (s, 1H), 6.13 (m, 1H),3.68 (t, 4H), 3.28 (t, 4H), 2.38 (s, 6H), 2.24 (s, 3H) 5 ¹H NMR (400MHz, CDCl₃) δ 8.11 (s, 1H), 7.33-7.32 (m, 549 (M + H) 2H), 7.26-7.22 (m,3H), 7.09 (d, 2H), 6.84 (d, 2H), 6.38 (s, 1H), 6.31 (s, 1H), 6.08 (s,1H), 4.39 (t, 2H), 3.69 (s, 2H), 3.35 (t, 4H), 3.22 (t, 4H), 2.83 (t,2H), 2.49 (s, 3H), 2.37 (s, 3H), 2.23 (s, 3H) 6 ¹H NMR (400 MHz, CDCl₃)δ 8.16 (s, 1H), 7.37 (d, 2H), 520 (M + H) 7.35-7.25 (m, ~3H, solventoverlap), 7.18 (d, 2H), 6.85 (d, 2H), 6.38 (s, 1H), 6.31 (s, 1H), 6.10(s, 1H), 4.37 (qn, 2H), 3.66 (t, 4H), 3.23 (t, 4H), 2.92 (t, 2H),2.59-2.52 (m, 2H), 2.38 (s, 3H), 2.23 (s, 3H) 7 ¹H NMR (400 MHz, CDCl₃)δ 8.13 (s, 1H), 7.33-7.24 (m, 536 (M + H) ~5H, solvent overlap), 7.11(d, 2H), 6.84 (d, 2H), 6.39 (s, 1H), 6.31 (s, 1H), 6.10 (s, 1H), 4.91(s, 2H), 4.37 (t, 2H), 4.06 (t, 2H), 3.66 (t, 4H), 3.23 (t, 4H), 2.37(s, 3H), 2.23 (s, 3H) 8 ¹H NMR (400 MHz, CDCl₃) δ 8.26 (s, 1H),7.31-7.29 (m, 536 (M + H) 2H), 7.26-7.21 (m, 3H), 7.09 (d, 2H), 6.85 (d,2H), 6.41 (s, 1H), 6.33 (s, 1H), 6.10 (s, 1H), 3.68 (t, 4H), 3.24 (t,4H), 2.47 (s, 3H), 2.40 (m, 1H), 2.39 (s, 3H), 2.25 (s, 3H), 1.60 (d,6H) 9 ¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.32 (d, 2H), 552 (M + H)7.24-7.21 (m, 3H), 7.06 (d, 2H), 6.82 (d, 2H), 6.38 (s, 1H), 6.31 (s,1H), 6.13 (s, 1H), 4.38 (t, 2H), 3.73 (t, 2H), 3.65 (t, 4H), 3.32 (s,3H), 3.22 (t, 4H), 2.38 (s, 3H), 2.37 (s, 3H), 2.23 (s, 3H) 10 ¹H NMR(400 MHz, CDCl₃): δ 8.19 (s, 1H), 7.30 (d, 2H), 665 (M + H) 7.24-7.20(m, 3H), 7.14-7.10 (m, 2H), 6.71 (d, 1H), 6.35 (s, 1H), 6.25 (s, 1H),6.13 (s, 1H), 3.97 (t, 2H), 3.82 (s, 3H), 3.71 (t, 4H), 3.53-3.50 (m,6H), 2.56 (m, 4H), 2.51 (t, 2H), 2.45 (m, 4H), 2.35 (s, 3H), 2.33 (s,3H), 2.21 (s, 3H), 1.95 (qn, 2H) 11 ¹H NMR (400 MHz, CDCl₃) δ 8.18 (s,1H), 7.29-7.22 (m, 541 (M − H) ~5H, solvent overlap), 7.20 (d, 1H), 7.04(dd, 1H), 6.92 (d, 1H), 6.38 (s, 1H), 6.31 (s, 1H), 6.14 (s, 1H), 3.82(s, 3H), 3.67 (t, 4H), 3.09 (t, 4H), 2.37 (s, 3H), 2.33 (s, 3H), 2.23(s, 3H) 12 ¹H NMR (400 MHz, CDCl₃) δ 8.40 (s, 1H), 7.45 (d, 2H), 498(M + H) 7.20 (s, 1H), 6.93 (d, 2H), 6.48 (d, 1H), 6.39-6.37 (m, 2H),6.32 (s, 1H), 6.20 (s, 1H), 3.77 (s, 3H), 3.67 (t, 4H), 3.26 (t, 4H),2.38 (s, 3H), 2.30 (s, 3H), 2.23 (s, 3H) 13 ¹H NMR (400 MHz, CDCl₃) δ8.25 (s, 1H), 7.29-7.26 (m, 514 (M + H) ~2H, solvent overlap), 7.22 (d,1H), 6.98 (d, 1H), 6.93-6.88 (m, 3H), 6.39 (s, 1H), 6.32 (s, 1H), 6.17(s, 1H), 3.78 (s, 3H), 3.66 (t, 4H), 3.24 (t, 4H), 2.38 (s, 3H), 2.31(s, 3H), 2.23 (s, 3H) 14 ¹H NMR (400 MHz, CD₃OD) δ 7.53 (d, 2H), 7.03(d, 2H), 472 (M − H) 6.48 (s, 1H), 6.44 (s, 1H), 6.04 (s, 1H), 3.80 (s,3H), 3.63 (t, 4H), 3.26 (m, 4H), 3.15 (m, 1H), 2.33 (s, 3H), 2.27 (s,3H), 2.24 (s, 3H), 1.15 (d, 6H) 15 ¹H NMR (400 MHz, CDCl₃) δ 8.43 (s,1H), 7.57 (d, 2H), 516 (M + H) 6.99 (d, 2H), 6.40 (s, 1H), 6.33 (s, 1H),6.00 (s, 1H), 3.98 (dd, 2H), 3.69-3.67 (m, 7H), 3.42 (t, 2H), 3.29 (m,4H), 3.13 (m, 1H), 2.38 (s, 3H), 2.26 (s, 3H), 2.24 (s, 3H), 1.79-1.69(m, 4H) 16 ¹H NMR (400 MHz, CDCl₃) δ 8.88 (broad s, 1H), 7.90 (d, 369(M + H) 1H), 7.84 (d, 1H), 7.63 (d, 1H), 7.62-7.49 (m, 2H), 7.40-7.34(m, 4H), 7.27-7.23 (m, ~3H, solvent overlap), 6.16 (s, 1H), 3.87 (s,3H), 2.35 (s, 3H) 17 ¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1H), 7.29 (m,2H), 609 (M + H) 7.26-7.22 (m, 3H), 7.14-7.09 (m, 2H), 6.71 (d, 1H),6.34 (s, 1H), 6.25 (s, 1H), 6.13 (s,1H), 4.03 (t, 2H), 3.81 (s, 3H),3.53 (m, 6H), 2.72 (t, 2H), 2.56 (t, 4H), 2.36 (s, 3H), 2.33 (s, 6H),2.32 (s, 3H), 2.21 (s, 3H) 18 ¹H NMR (400 MHz, CDCl₃) δ 7.98 (s, 1H),7.29-7.23 (m, 508 (M + H) 5H), 7.01 (d, 2H), 6.83 (d, 2H), 6.79 (s, 1H),6.39 (s, 1H), 6.31 (s, 1H), 3.89 (s, 3H), 3.66 (t, 4H), 3.22 (t, 4H),2.38 (s, 3H), 2.23 (s, 3H), 2.01 (s, 3H) 19 ¹H NMR (400 MHz, CDCl₃) δ8.18 (s, 1H), 7.30 (d, 2H), 678 (M + H) 7.24-7.20 (m, 3H), 7.13-7.10 (m,2H), 6.71 (d, 1H), 6.34 (s, 1H), 6.25 (s, 1H), 6.13 (s, 1H), 3.96 (t,2H), 3.81 (s, 3H), 3.53 (m, 6H), 2.57-2.40 (broad m, ~14H), 2.36 (s,3H), 2.33 (s, 3H), 2.29 (s, 3H), 2.21 (s, 3H), 1.95 (qn, 2H) 20 ¹H NMR(400 MHz, CDCl₃) δ 8.21 (s, 1H), 7.32-7.30 (m, 536 (M + H) 2H),7.26-7.21 (m, 3H), 7.09 (d, 2H), 6.84 (d, 2H), 6.38 (s, 1H), 6.32 (s,1H), 6.16 (s, 1H), 3.85 (s, 3H), 3.66 (t, 4H), 3.22 (t, 4H), 3.02 (m,1H), 2.37 (s, 3H), 2.23 (s, 3H), 1.32 (d, 6H) 21 ¹H NMR (400 MHz, CDCl₃)δ 8.64 (s, 1H), 7.49 (d, 1H), 540 (M − H) 7.30 (d, 2H), 7.21-7.19 (m,3H), 6.92 (d, 1H), 6.70 (dd, 1H), 6.39 (s, 1H), 6.31 (s, 1H), 6.13 (s,1H), 3.83 (s, 3H), 3.65 (t, 4H), 3.22 (t, 4H), 2.37 (s, 3H), 2.33 (s,3H), 2.23 (s, 3H) 22 ¹H NMR (400 MHz, CDCl₃): δ 8.26 (s, 1H), 7.30-7.22(m, 524 (M + H) ~5H, solvent overlap), 7.05 (d, 1H), 6.84 (s, 1H), 6.72(d, 1H), 6.38 (s, 1H), 6.32 (s, 1H), 6.14 (s, 1H), 3.81 (s, 3H), 3.65(m, 4H), 3.60 (s, 1H), 2.94 (m, 4H), 2.37 (s, 3H), 2.33 (s, 3H), 2.21(s,3H) 23 ¹H NMR (400 MHz, CDCl₃) δ 8.17 (s, 1H), 7.31-7.26 (m, 361 (M +H) 5H), 6.98 (t, 1H), 6.81 (d, 1H), 6.55 (d, 1H), 6.13 (s, 1H), 4.55 (d,2H), 3.81 (s, 3H), 3.03 (t, 2H), 2.34 (s, 3H) 24 ¹H NMR (400 MHz, CDCl₃)δ 8.08 (s, 1H), 7.30-7.09 (m, 586 (M + H) ~5H, solvent overlap), 7.16(d, 1H), 7.01 (d, 1H), 6.91 (d, 1H), 6.38 (s, 1H), 6.31 (s, 1H), 6.14(s, 1H), 4.40 (t, 2H), 3.73 (t, 2H), 3.69 (m, 4H), 3.33 (s, 3H), 3.09(m, 4H), 2.39 (s, 3H), 2.37 (s, 3H), 2.23 (s, 3H) 25 ¹H NMR (400 MHz,CDCl₃) δ 8.25 (s, 1H), 7.55 (d, 2H), 518 (M + H) 6.98 (d, 2H), 6.39 (s,1H), 6.32 (s, 1H), 5.98 (s, 1H), 4.31 (t, 2H), 3.69-3.64 (m, 6H),3.29-3.24 (m, 8H), 2.38 (s, 3H), 2.30 (s, 3H), 2.24 (s, 3H), 1.18 (d,6H) 26 ¹H NMR (400 MHz, CDCl₃) δ 8.54 (s, 1H), 7.46 (d, 1H), 586 (M + H)7.31 (d, 2H), 7.25-7.18 (m, 3H), 6.91 (d, 1H), 6.70 (dd, 1H), 6.39 (s,1H), 6.31 (s, 1H), 6.13 (s, 1H), 4.41 (t, 2H), 3.75 (t, 2H), 3.65 (m,4H), 3.33 (s, 3H), 3.22 (m, 4H), 2.39 (s, 3H), 2.37 (s, 3H), 2.23 (s,3H) 27 ¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H), 7.32 (d, 2H), 564 (M − H)7.25-7.21 (m, 3H), 7.06 (d, 2H), 6.82 (d, 2H), 6.38 (s, 1H), 6.31 (s,1H), 6.13 (s, 1H), 4.39 (t, 2H), 3.77 (t, 2H), 3.65 (t, 4H), 3.47 (q,2H), 3.22 (t, 4H), 2.39 (s, 3H), 2.37 (s, 3H), 2.23 (s, 3H), 1.14 (t,3H) 28 ¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 7.31 (d, 2H), 564 (M − H)7.24-7.21 (m, 3H), 7.07 (d, 2H), 6.83 (d, 2H), 6.38 (s, 1H), 6.31 (s,1H), 6.12 (s, 1H), 4.32 (t, 2H), 3.65 (t, 4H), 3.41 (t, 2H), 3.35 (s,3H), 3.22 (t, 4H), 2.37-2.36 (m, 6H), 2.36 (s, 3H), 2.04 (m, 2H) 29 ¹HNMR (400 MHz, CDCl₃) δ 8.92 (m, 1H), 8.74 (broad s, 412 (M − H) 1H),8.12 (d, 1H), 7.91 (d, 1H), 7.57 (t, 1H), 7.42-7.34 (m, 4H), 7.29-7.26(m, 3H), 6.17 (s, 1H), 4.44 (t, 2H), 3.78 (t, 2H), 3.35 (s, 3H), 2.50(s, 3H) 30 ¹H NMR (400 MHz, CDCl₃) δ 9.24 (s, 1H), 8.78 (broad s, 412 (M− H) 1H), 8.56 (d, 1H), 7.75 (d, 1H), 7.62 (m, 2H), 7.46 (t, 1H),7.36-7.34 (m, 2H), 7.26-7.23 (m, 3H), 6.17 (s, 1H), 4.44 (t, 2H), 3.79(t, 2H), 3.35 (s, 3H), 2.24 (s, 3H) 31 ¹H NMR (400 MHz, CDCl₃) δ 8.86(d, 1H), 8.15-8.09 (dd, 368 (M − H) 2H), 7.49-7.44 (m, 2H), 7.38 (t,1H), 7.31-7.26 (m, 3H), 7.05-7.03 (m, 3H), 6.13 (s, 1H), 3.90 (s, 3H),2.35 (S, 3H) 32 ¹H NMR (400 MHz, CDCl₃) δ 8.93 (d, 1H), 8.81 (broad s,370 (M + H) 1H), 8.14 (d, 1H), 7.92 (d, 1H), 7.58 (t, 1H), 7.43-7.34 (m,4H), 7.29-7.28 (m, 3H), 6.16 (s, 1H), 3.87 (s, 3H), 2.36 (s, 3H) 33 ¹HNMR (400 MHz, CDCl₃) δ 8.42 (d, 1H), 7.26-7.22 (m, 320 (M + H) 3H),7.21-7.19 (m, 4H), 7.12 (d, 2H), 6.15 (s, 1H), 3.83 (s, 3H), 2.34 (s,3H) 34 ¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 7.32-7.21 (m, 520 (M − H)5H), 7.07 (d, 2H), 6.83 (d, 2H), 6.38 (s, 1H), 6.31 (s, 1H), 6.12 (s,1H), 4.26 (q, 2H), 3.65 (t, 4H), 3.22 (t, 4H), 2.37 (s, 3H), 2.36 (s,3H), 2.33 (s, 3H), 1.41 (t, 3H) 35 ¹H NMR (400 MHz, CDCl₃) δ 10.17 (s,1H), 7.22 (d, 2H), 534 (M − H) 7.10-7.03 (m, 5H), 6.79 (d, 2H), 6.47 (s,1H), 6.37 (s, 1H), 6.08 (s, 1H), 4.18 (t, 2H), 3.55 (m, 4H), 3.11 (m,4H), 2.33 (s, 3H), 2.25 (s, 3H), 2.17 (s, 3H), 1.70 (q, 2H), 0.91 (t,3H) 36 ¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 7.30 (d, 2H), 550 (M + H)7.26-7.20 (m, 3H), 7.07 (d, 2H), 6.83 (d, 2H), 6.38 (s, 1H), 6.31 (s,1H), 6.12 (s, 1H), 4.19 (t, 2H), 3.65 (t, 4H), 3.22 (t, 4H), 2.37 (s,3H), 2.35 (s, 3H), 2.23 (s, 3H), 1.17 (m, 2H), 1.43 (m, 2H), 0.98 (t,3H) 37 ¹H NMR (400 MHz, CDCl₃) δ 8.60 (s, 1H), 8.49 (s, 1H), 370 (M + H)8.15 (s, 1H), 8.02 (d, 1H), 7.69 (d, 1H), 7.62 (t, 1H), 7.51 (t, 1H),7.31 (d, 2H), 7.21-7.16 (m, 3H), 6.17 (s, 1H), 3.86 (s, 3H), 2.36 (s,3H) 38 ¹H NMR (400 MHz, CDCl₃) δ 8.20 (m, 2H), 7.50 (t, 1H), 480 (M + H)7.31 (d, 2H), 7.23 (m, 3H), 7.10 (d, 2H), 6.84 (d, 2H), 6.70-6.64 (m,2H), 6.13 (s, 1H), 3.82 (s, 3H), 3.68 (t, 4H), 3.23 (t, 4H), 2.33 (s,3H) 39 ¹H NMR (400 MHz, CDCl₃) δ 8.19 (s, 1H), 7.39 (t, 1H), 494 (M + H)7.31 (d, 2H), 7.21-7.31 (m, 3H), 7.10 (d, 2H), 6.84 (d, 2H), 6.52-6.47(dd, 2H), 6.13 (s, 1H), 3.82 (s, 3H), 3.67 (t, 4H), 3.23 (t, 4H), 2.41(s, 3H), 2.33 (s, 3H) 40 ¹H NMR (400 MHz, CDCl₃) δ 8.19 (s, 1H), 8.07(d, 1H), 494 (M + H) 7.31 (d, 2H), 7.25-7.21 (m, 3H), 7.10 (d, 2H), 6.85(d, 2H), 6.50 (d, 2H), 6.13 (s, 1H), 3.82 (s, 3H), 3.67 (t, 4H), 3.23(t, 4H), 2.33 (s, 3H), 2.28 (s, 3H) 41a ¹H NMR (400 MHz, CDCl₃) δ 8.26(s, 1H), 7.31-7.29 (d, 548 (M + H) 2H), 7.24-7.21 (m, 2H), 7.11 (d, 2H),6.84 (d, 2H), 6.38 (s, 1H), 6.31 (s, 1H), 6.09 (s, 1H), 4.39 (s, 3H),3.65 (t, 4H), 3.22 (t, 4H), 2.81 (m, 2H), 2.37 (s, 3H), 2.31 (s, 3H),1.85 (broad s, 4H), 1.74 (broad s, 2H) 41b ¹H NMR (400 MHz, CDCl₃) δ9.10 (s, 1H), 8.09 (s, 1H), 548 (M + H) 7.60 (d, 3H), 7.41-7.26 (m, H),6.98 (d, 2H), 6.39 (s, 1H), 6.32 (s, 3H), 4.78 (broad s, 2H), 3.68 (t,4H), 3.27 (t, 4H), 2.93 (m, 2H), 2.38 (s, 3H), 2.23 (s, 3H), 1.89-1.83(m, 4H), 1.73 (m, 2H) 42 ¹H NMR (400 MHz, CDCl₃) δ 9.38 (broad s, 1H),414 (M + H) 8.98 (broad s, 1H), 8.57 (broad s, 1H), 7.64-7.51 (m, 4H),7.35 (d, 2H), 7.24-7.19 (m, 3H), 6.17 (s, 1H), 4.45 (t, 2H), 3.78 (t,2H), 3.35 (s, 3H), 3.41 (s, 3H) 43 ¹H NMR (400 MHz, CDCl₃) δ 9.41 (s,1H), 9.06 (s, 1H), 368 (M − H) 8.57 (d, 1H), 7.64-7.53 (m, 4H),7.34-7.33 (m, 2H), 7.31-7.18 (m, 3H), 6.17 (s, 1H), 3.88 (s, 3H), 2.36(s, 3H) 44 ¹H NMR (400 MHz, CDCl₃) δ 8.45 (s, 1H), 7.56-7.68 (m, 367 (M− H) 4H), 7.44-7.34 (m, 2H), 7.32 (d, 2H), 7.24-7.15 (m, 4H), 6.15 (s,1H), 3.84 (s, 3H), 2.34 (s, 3H) 45 ¹H NMR (400 MHz, CDCl₃) δ 9.11 (s,1H), 8.18 (s, 1H), 494 (M + H) 7.32 (d, 2H), 7.26-7.23 (merged withsolvent, ~3H), 7.12 (d, 2H), 6.94 (d, 1H), 6.84 (d, 2H), 6.38 (s, 1H),6.31 (s, 1H), 3.91 (s, 3H), 3.66 (t, 4H), 3.23 (t, 4H), 2.37 (s, 3H),2.23 (s, 3H) 46 ¹H NMR (400 MHz, CDCl₃) δ 9.10 (s, 1H), 8.38 (d, 1H),494 (M + H) 7.62 (d, 2H), 7.55 (d, 2H), 7.36 (t, 2H), 7.31 (s, 1H),7.25-7.22 (merged with solvent, ~ 1H), 7.00 (d, 2H), 6.40 (s, 1H), 6.32(s, 1H), 4.05 (s, 3H), 3.69 (t, 4H), 3.29 (t, 4H), 2.38 (s, 3H), 2.24(s, 3H) 47 ¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 7.32 (d, 2H), 538(M + H) 7.28-7.22 (m, 3H), 7.11-7.09 (m, 3H), 6.84 (d, 2H), 6.38 (s,1H), 6.33-6.31 (m, 2H), 4.43 (t, 2H), 3.72 (t, 2H), 3.65 (t, 4H), 3.34(s, 3H), 3.22 (t, 4H), 2.37 (s, 3H), 2.23 (s, 3H) 48 ¹H NMR (400 MHz,CDCl₃) δ 8.15 (s, 1H), 7.36-7.29 (m, 583 (M − H) 6H), 7.27-7.23 (m, 3H),7.06 (d, 4H), 6.82 (d, 2H), 6.38 (s, 1H), 6.30 (s, 1H), 6.20 (s, 1H),5.51 (s, 1H), 3.64 (t, 4H), 3.21 (t, 4H), 2.37 (s, 3H), 2.26 (s, 3H),2.23 (s, 3H) 49 ¹H NMR (400 MHz, CDCl₃) δ 8.85 (s, 1H), 8.01 (d, 1H),468 (M + H) 7.61 (d, 1H), 7.46 (t, 1H), 7.35-7.32 (m, 4H), 7.25-7.23 (m,3H), 7.12 (d, 1H), 6.15 (s, 1H), 3.86 (s, 3H), 3.13 (broad s, 4H), 2.70(broad s, 4H), 2.41 (s, 3H), 2.35 (s, 3H) 50 ¹H NMR (400 MHz, CDCl₃) δ11.93 (broad s, 1H), 9.42 (s, 494 (M + H) 1H), 7.61 (d, 2H), 7.55 (d,2H), 7.42-7.32 (m, 3H), 6.98 (d, 2H), 6.39 (s, 1H), 6.32 (s, 1H), 6.21(d, 1H), 3.68 (t, 4H), 3.29 (t, 4H), 2.41 (s, 3H), 2.38 (s, 3H), 2.24(s, 3H) 51 ¹H NMR (400 MHz, CDCl₃) δ 8.17 (s, 1H), 7.32-7.23 (m, 522(M + H) 4H), 6.97 (d, 2H), 6.89 (d, 2H), 6.38 (s, 1H), 6.31 (s, 1H),6.13 (s, 1H), 3.82 (s, 3H), 3.63 (t, 4H), 2.95 (t, 4H), 2.37 (s, 3H),2.33 (s, 3H), 2.26 (s, 3H), 2.23 (s, 3H) 52 ¹H NMR (400 MHz, CDCl₃) δ8.05 (s, 1H), 7.34-7.32 (m, 566 (M + H) 2H), 7.25-7.24 (m, 3H), 7.06 (d,2H), 6.82 (d, 2H), 6.38 (s, 1H), 6.31 (s, 1H), 6.20 (s, 1H), 4.93 (s,2H), 3.84 (s, 3H), 3.65 (t, 4H), 3.21 (t, 4H), 2.37 (s, 3H), 2.31 (s,3H), 2.23 (s, 3H) 53 ¹H NMR (400 MHz, CDCl₃) δ 8.23 (s, 1H), 7.31 (d,2H), 522 (M + H) 7.27-7.24 (m, 3H), 7.10 (d, 2H), 6.84 (d, 2H), 6.39 (s,1H), 6.31 (s, 1H), 6.16 (s, 1H), 3.82 (s, 3H), 3.65 (t, 4H), 3.23 (t,4H), 2.67 (q, 2H), 237 (s, 3H), 2.23 (s, 3H), 1.32 (t, 3H) 54 ¹H NMR(400 MHz, CDCl₃) δ 8.13 (s, 1H), 7.36-7.33 (m, 566 (M + H) 3H),7.27-7.25 (m, 2H), 7.08 (d, 2H), 6.84 (d, 2H), 6.40 (s, 1H), 6.32 (s,1H), 6.19 (s, 1H), 4.42 (t, 2H), 3.74 (t, 2H), 3.67 (t, 4H), 3.34 (s,3H), 3.23 (t, 4H), 2.27 (m, 2H), 2.39 (s, 3H), 2.25 (s, 3H), 1.34 (t,3H) 55 ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 1H), 7.40 (m, 5H), 566 (M + H)6.85 (d, 2H), 6.59 (d, 2H), 6.39 (s, 1H), 6.30 (s, 1H), 6.05 (d, 1H),4.16 (q, 2H), 3.63 (m, 4H), 3.30 (m, 4H), 2.37 (s, 6H), 2.23 (s, 3H),1.15 (t, 3H) 56 ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 1H), 7.39 (s, 5H),552 (M + H) 6.85 (d, 2H), 6.61 (d, 2H), 6.39 (s, 1H), 6.33 (s, 1H), 6.05(s, 1H), 3.71 (s, 3H), 3.65 (t, 4H), 3.30 (t, 4H), 2.38 (s, 6H), 2.23(s, 3H) 57 ¹H NMR (400 MHz, CDCl₃) δ 8.01 (s, 1H), 7.33-7.28 (m, 572(M + H) 2H), 7.19-7.09 (m, 5H), 6.84 (d, 2H), 6.39 (s, 1H), 6.32 (s,1H), 6.28 (d, 1H), 4.48 (t, 2H), 3.75 (t, 2H), 3.66 (t, 4H), 3.35 (s,3H), 3.23 (t, 4H), 2.38 (s, 3H), 2.23 (s, 3H) 58 ¹H NMR (400 MHz, CDCl₃)δ 9.10 (s, 1H), 8.46 (d, 1H), 572 (M + H) 7.62 (d, 2H), 7.55-7.52 (m,1H), 7.44 (dd, 1H), 7.30-7.27 (m, 1H), 7.21 (t, 1H), 7.09 (d, 2H), 6.41(s, 1H), 6.34 (s, 1H), 4.64 (t, 2H), 3.74 (t, 2H), 3.70 (t, 4H), 3.34(s, 3H), 3.30 (t, 4H), 2.39 (s, 3H), 2.25 (s, 3H) 59 ¹H NMR (400 MHz,CDCl₃) δ 8.20 (s, 1H), 7.26-7.23 (m, 572 (M + H) 4H), 7.15-7.12 (d, 2H),7.08 (d, 1H), 6.88 (d, 2H), 6.39 (s, 1H), 6.31 (s, 1H), 6.29 (d, 1H),4.42 (t, 2H), 3.71-7.65 (m, 6H), 3.33 (s, 3H), 3.26 (m, 4H), 2.37 (s,3H), 2.24 (s, 3H) 60 ¹H NMR (400 MHz, CDCl₃) δ 8.22 (s, 1H), 7.32-7.30(dd, 363 (M + H) 2H), 7.24-7.16 (m, 7H), 7.07-7.04 (m, 1H), 6.14 (s,1H), 4.41-4.39 (t, 2H), 3.75-3.72 (t, 2H), 3.27 (s, 3H), 2.39 (s, 3H) 61¹H NMR (400 MHz, CDCl₃) δ 9.01 (s, 1H), 8.21 (dd, 1H), 476 (M + H) 7.57(d, 2H), 7.03 (s, 1H), 6.97 (d, 2H), 6.39 (s, 1H), 6.35-6.32 (m, 2H),5.04 (s, 2H), 3.80 (s, 3H), 3.68 (t, 4H), 3.27 (t, 4H), 2.38 (s, 3H),2.23 (s, 3H) 62 ¹H NMR (400 MHz, CDCl₃) δ 8.18 (s, 1H), 7.32-7.30 (m,538 (M + H) 3H), 7.28-7.26 (m, 2H), 7.09 (d, 2H), 6.84 (d, 2H), 6.38 (s,1H), 6.31 (S, 1H), 6.20 (s, 1H), 5.60 (s, 2H), 3.65 (t, 4H), 3.40 (s,3H), 3.22 (t, 4H), 2.42 (s, 3H), 2.37 (s, 3H), 2.23 (s, 3H) 63 ¹H NMR(400 MHz, CDCl₃) δ 8.27 (s, 1H), 7.36-7.34 (m, 522 (M − H) 2H),7.30-7.26 (m, 3H), 7.17-7.14 (m, 3H), 6.86 (d, 2H), 6.41-6.39 (m, 2H),6.32 (s, 1H), 5.57 (s, 2H), 3.66 (t, 4H), 3.34 (s, 3H), 3.23 (t, 4H),2.38 (s, 3H), 2.24 (s, 3H) 64 ¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H),7.30 (m, 2H), 538 (M + H) 7.26-7.24 (m, 3H), 7.02 (d, 2H), 6.83 (d, 2H),6.74 (s, 1H), 6.39 (s, 1H), 6.30 (d, 1H), 6.17 (d, 1H), 4.37 (t, 2H),4.00 (d, 2H), 3.64 (m, 4H), 3.22 (m, 4H), 2.39 (s, 3H), 2.37 (s, 3H),2.23 (s, 3H) 65 ¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1H), 7.30-7.28 (m,579 (M + H) 2H), 7.26-7.22 (m, 3H), 7.05 (d, 2H), 6.82 (d, 2H), 6.39 (s,1H), 6.31 (s, 1H), 6.24 (broad s, 1H), 6.16 (s, 1H), 4.37 (t, 2H),3.66-3.58 (m, 6H), 3.23 (m 4H), 2.37 (s, 6H), 2.23 (s, 3H), 1.94 (s, 3H)66 ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 7.50 (d, 1H), 524 (M + H)7.33-7.31 (m, 3H), 7.27-7.25 (m, 2H), 7.10-7.07 (m, 2H), 6.84 (d, 2H),6.75 (s, 1H), 6.39-6.36 (m, 2H), 6.30 (m, 1H), 4.41 (t, 2H), 3.97 (t,2H), 3.64 (m, 4H), 3.34-3.17 (m, 4H), 2.37 (s, 3H), 2.23 (s, 3H) 67 ¹HNMR (400 MHz, CDCl₃) δ 8.20 (s, 1H), 7.26-7.21 (m, 544 (M + H) 3H), 7.06(d, 1H), 6.99 (d, 1H), 6.93-6.87 (m, 3H), 6.38 (s, 1H), 6.35 (d, 1H),6.31 (s, 1H), 4.40 (t, 2H), 3.70-3.65 (m, 6H), 3.32 (s, 3H), 3.24 (t,4H), 2.37 (s, 3H), 2.23 (s, 3H) 68 ¹H NMR (400 MHz, CDCl₃) δ 8.29 (s,1H), 7.56 (d, 2H), 518 (M + H) 6.98 (t, 3H), 6.39 (s, 1H), 6.32 (s, 1H),6.05 (d, 1H), 4.37 (t, 2H), 3.68 (m, 4H), 3.62 (t, 2H), 3.29 (s, 3H),3.27 (m, 4H), 2.63 (d, 2H), 2.38 (s, 3H), 2.24 (s, 3H), 1.80 (m, 1H),0.84 (d, 6H) 69 ¹H NMR (400 MHz, CDCl₃) δ 8.03 (broad s, 1H), 580 (M +H) 7.34-7.31 (m, 2H), 7.25-7.23 (m, 3H), 7.06 (d, 2H), 6.83 (d, 2H),6.38 (s, 1H), 6.31 (s, 1H), 6.19 (s, 1H), 4.92 (s, 2H), 4.30 (q, 2H),3.65 (t, 4H), 3.21 (t, 4H), 2.37 (s, 3H), 2.31 (s, 3H), 2.23 (s, 3H),1.33 (t, 3H) 70 ¹H NMR (400 MHz, CDCl₃) δ 8.22 (broad s, 1H), 7.33 (s,572 (M + H) 1H), 7.20-7.16 (m, 5H), 7.07 (d, 1H), 6.87 (d, 2H), 6.38 (s,1H), 6.31 (d, 2H), 4.42 (t, 2H), 3.72-3.65 (m, 6H), 3.33 (s, 3H), 3.24(t, 4H), 2.37 (s, 3H), 2.23 (s, 3H) 71 ¹H NMR (400 MHz, CDCl₃) δ 9.07(s, 1H), 8.44 (d, 1H), 572 (M + H) 7.61 (d, 2H), 7.55 (s, 1H), 7.44 (d,2H), 7.29 (d, 1H), 7.19 (d, 1H), 6.99 (d, 2H), 6.39 (s, 1H), 6.32 (s,1H), 4.59 (t, 2H), 3.72-3.67 (m, 6H), 3.33 (s, 3H), 3.29 (t, 4H), 2.38(s, 3H), 2.24 (s, 3H) 72 ¹H NMR (400 MHz, CDCl₃) δ 8.19 (s, 1H), 7.26(q, 3H), 544 (M + H) 7.17 (d, 1H), 7.12 (d, 1H), 7.08 (d, 1H), 6.90 (s,1H), 6.88 (s, 1H), 6.39 (s, 1H), 6.31 (t, 2H), 4.42 (t, 2H), 3.69 (m,6H), 3.33 (s, 3H), 3.24 (t, 4H), 2.38 (s, 3H), 2.24 (s, 3H) 73 ¹H NMR(400 MHz, CDCl₃) δ 8.05 (s, 1H), 7.35 (d, 2H), 566 (M + H) 7.29 (m, 3H),7.07 (d, 2H), 6.99 (d, 1H), 6.83 (d, 2H), 6.39 (d, 2H), 6.31 (s, 1H),4.94 (s, 2H), 4.28 (q, 2H), 3.65 (t, 4H), 3.22 (t, 4H), 2.37 (s, 3H),2.23 (s, 3H), 1.32 (t, 3H) 74 ¹H NMR (400 MHz, CDCl₃) δ 8.02 (s, 1H),7.34 (m, 3H), 552 (M + H) 7.25 (m, 2H), 7.07 (d, 2H), 6.99 (s, 1H), 6.83(d, 2H), 6.38 (d, 2H), 6.30 (s, 1H), 4.95 (s, 2H), 3.83 (s, 3H), 3.65(m, 4H), 3.22 (m, 4H), 2.37 (s, 3H), 2.32 (s, 3H) 75 ¹H NMR (400 MHz,CDCl₃) δ 8.24 (s, 1H), 7.33-7.25 (m, 537 (M + H) 5H), 7.07 (m, 3H), 6.83(d, 2H), 6.43 (d, 1H), 6.39 (s, 1H), 6.31 (s, 1H), 6.03 (s, 1H), 5.63(s, 1H), 4.88 (s, 2H), 3.65 (t, 4H), 3.22 (t, 4H), 2.38 (s, 3H), 2.23(s, 3H) 76 ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 7.34-7.27 (m, 549 (M− H) 4H), 7.08 (m, 3H), 6.84 (d, 2H), 6.43 (d, 1H), 6.39 (s, 1H), 6.31(s, 1H), 6.01 (s, 1H), 5.63 (s, 1H), 4.86 (s, 2H), 3.65 (t, 4H), 3.23(t, 4H), 2.83 (d, 3H), 2.38 (s, 3H), 2.23 (s, 3H) 77 ¹H NMR (400 MHz,CDCl₃) δ 8.06 (s, 1H), 7.23-7.32 (q, 594 (M + H) 2H), 7.23 (d, 2H), 7.05(d, 2H), 6.83 (d, 2H), 6.39 (s, 1H), 6.31 (s, 1H), 6.19 (s, 1H), 5.15(q, 1H), 4.89 (s, 2H), 3.65 (t, 4H), 3.21 (t, 4H), 2.37 (s, 3H), 2.31(s, 3H), 2.23 (s, 3H), 1.30 (m, 7H) 78 ¹H NMR (400 MHz, CDCl₃) δ 8.12(broad s, 1H), 7.32 (d, 578 (M − H) 2H), 7.23 (m, 3H), 7.06 (d, 2H),6.83 (d, 2H), 6.38 (s, 1H), 6.30 (s, 1H), 6.18 (s, 1H), 4.43 (m, 2H),3.71 (m, 2H), 3.65 (m, 4H), 3.32 (s, 3H), 3.21 (m, 5H), 2.37 (s, 3H),2.23 (s, 3H), 1.30 (d, 6H) 79 ¹H NMR (400 MHz, CDCl₃) δ 8.86 (s, 1H),7.76 (d, 1H), 368 (M − H) 7.70 (broad s, 1H), 7.64 (d, 1H), 7.48 (t,1H), 7.60-7.40 (m, merged with solvent, 3H), 7.34-7.33 (m, 2H),7.26-7.23 (m, 2H), 6.17 (s, 1H), 3.87 (s, 3H), 2.36 (s, 3H) 80 ¹H NMR(400 MHz, CDCl₃) δ 8.27 (s, 1H), 7.40-7.35 (m, 552 (M + H) 3H), 7.31 (d,2H), 7.22 (d, 2H), 6.89 (d, 2H), 6.39 (s, 1H), 6.31 (s, 1H), 6.14 (s,1H), 3.67-3.63 (m, 6H), 3.35 (s, 3H), 3.24 (t, 4H), 3.11 (t, 2H), 2.37(s, 3H), 2.23 (s, 3H), 2.08 (s, 3H) 81 ¹H NMR (400 MHz, CDCl₃) δ 8.25(broad s, 1H), 347 (M − H) 7.33-7.31 (m, 2H), 7.25-7.10 (m 7H),7.10-7.07 (m, 2H), 6.33-6.32 (d, 1H), 4.46-4.42 (t, 2H), 3.74-3.70 (t,2H), 3.34 (s, 3H) 82 ¹H NMR (400 MHz, CDCl₃) δ 7.33-7.25 (m, 5H), 7.05(d, 315 (M + H) 1H), 6.32 (broad s, 1H), 6.27-6.26 (d, 1H), 4.41-4.39(t, 2H), 3.71-3.69 (t, 2H), 3.33 (s, 3H), 2.90-2.85 (q, 2H), 1.36-1.30(q, 2H), 0.85-0.81 (t, 3H) 83 ¹H NMR (400 MHz, CDCl₃) δ 8.34 (s, 1H),7.56 (d, 2H), 504 (M + H) 6.98 (d, 3H), 6.39-6.32 (d, 2H), 6.16 (d, 1H),4.34 (t, 2H), 3.69-3.62 (m, 6H), 3.33-3.27 (m, 8H), 2.38 (s, 3H), 2.24(s, 3H), 1.20 (d, 6H) 84 ¹H NMR (400 MHz, CDCl₃) δ 8.28 (s, 1H), 7.33(d, 2H), 551 (M + H) 7.28-7.22 (m, 3H), 7.14 (d, 2H), 7.04 (d, 1H), 6.85(d, 2H), 6.39 (s, 1H), 6.33-6.31 (m, 2H), 4.35 (t, 2H), 3.65 (t, 4H),3.23 (t, 4H), 2.66 (t, 2H), 2.38 (s, 3H), 2.26 (s, 6H), 2.23 (s, 3H) 85¹H NMR (400 MHz, CDCl₃) δ 9.13 (s, 1H), 8.43 (d, 1H), 551 (M + H) 7.63(d, 2H), 7.56 (d, 2H), 7.43-7.35 (m, 3H), 7.23 (m, 1H), 7.00 (d, 2H),6.40 (s, 1H), 6.33 (s, 1H), 4.52 (t, 2H), 3.69 (t, 4H), 3.29 (t, 4H),2.69 (t, 2H), 2.38 (s, 3H), 2.33 (s, 6H), 2.24 (s, 3H) 86 ¹H NMR (400MHz, CDCl₃) δ 8.17 (s, 1H), 7.31-7.29 (m, 565 (M + H) 2H), 7.26-7.21 (m,merged with solvent, ~3H), 7.08 (d, 2H), 6.83 (d, 2H), 6.38 (s, 1H),6.31 (s, 1H), 6.13 (s, 1H), 4.32 (t, 2H), 3.65 (t, 4H), 3.22 (t, 4H),2.65 (t, 2H), 2.37 (s, 6H), 2.31 (s, 6H), 2.23 (s, 3H) 87 ¹H NMR (400MHz, CDCl₃) δ 8.08 (s, 1H), 7.23-7.21 (m, 558 (M + H) 3H), 7.02-6.93 (m,3H), 6.87 (d, 2H), 6.40 (d, 2H), 6.31 (s, 1H), 4.94 (s, 2H), 3.82 (s3H), 3.66 (t, 4H), 3.24 (t, 4H), 2.37 (s, 3H), 2.23 (s, 3H) 88 ¹H NMR(400 MHz, CDCl₃) δ 8.30 (s, 1H), 7.54 (d, 2H), 518 (M + H) 6.99-6.91 (m,3H), 6.40-6.33 (d, 2H), 6.25 (d, 1H), 4.85 (s, 2H), 3.80 (s, 3H), 3.68(t, 4H), 3.36 (m, 1H), 3.28 (t, 4H), 2.38 (s, 3H), 2.24 (s, 3H), 1.21(d, 6H) 89 ¹H NMR (400 MHz, CDCl₃) δ 9.05 (s, 1H), 8.01 (d, 1H), 532(M + H) 7.58 (d, 2H), 6.97 (d, 2H), 6.83 (d, 1H), 6.39 (s, 1H), 6.32 (s,1H), 4.99 (s, 2H), 3.80 (s, 3H), 3.68 (t, 4H), 3.27 (t, 4H), 2.67 (d,2H), 2.41 (s, 3H), 2.35 (s, 3H), 1.81 (t, 1H), 0.92 (d, 6H) 90 ¹H NMR(400 MHz, CDCl₃) δ 8.18 (s, 1H), 7.33-7.26 (m, 526 (M + H) 5H), 7.07 (d,2H), 6.83 (d, 2H), 6.38 (s, 1H), 6.31 (s, 1H), 3.80 (s, 3H), 3.65 (t,4H), 3.23 (t, 4H), 2.37 (s, 3H), 2.30 (s, 3H), 2.23 (s, 3H) 91 ¹H NMR(400 MHz, CDCl₃) δ 8.58 (s, 1H), 8.17 (s, 1H), 585 (M + H) 7.63 (t, 1H),7.36 (d, 2H), 7.32-7.22 (m, 3H), 7.18 (t, 1H), 7.05 (d, 2H), 6.92 (d,1H), 6.82 (d, 2H), 6.39 (s, 1H), 6.24 (d, 2H), 5.61 (s, 2H), 3.62 (s,4H), 3.21 (s, 4H), 2.38 (s, 3H), 2.36 (s, 3H), 2.22 (s, 3H) 92 ¹H NMR(400 MHz, CDCl₃) δ 8.54 (s, 1H), 7.46 (d, 1H), 586 (M + H) 7.31 (d, 2H),7.25-7.19 (m, 3H), 6.91-6.90 (d, 1H), 6.71-6.68 (dd, 1H), 6.39 (s, 1H),6.30 (s, 1H), 6.13 (s, 1H), 4.40 (t, 2H), 3.75 (t, 2H), 3.65 (t, 4H),3.32 (s, 3H), 3.22 (t, 4H), 2.38 (d, 6H), 2.23 (s, 3H) 93 ¹H NMR (400MHz, CDCl₃) δ 8.54 (d, 1H), 8.50 (s, 1H), 585 (M + H) 8.16 (s, 1H),7.40-7.34 (m, 3H), 7.32-7.26 (m, 4H), 7.08 (d, 2H), 6.84 (d, 2H), 6.40(s, 1H), 6.33 (s, 1H), 6.26 (s, 1H), 5.56 (s, 2H), 3.64 (m, 4H), 3.22(m, 4H), 2.40 (s, 3H), 2.30 (s, 3H), 2.24 (s, 3H) 94 ¹H NMR (400 MHz,CDCl₃) δ 8.08 (s, 1H), 7.35-7.24 (m, 570 (M + H) 5H), 7.05 (d, 2H), 6.82(d, 2H), 6.39 (s, 1H), 6.31 (s, 1H), 4.36 (t, 2H), 3.73 (t, 2H), 3.65(t, 4H), 3.33 (s, 3H), 3.22 (t, 4H), 2.36 (d, 6H), 2.23 (s, 3H) 95 ¹HNMR (400 MHz, CDCl₃) δ 8.31 (s, 1H), 8.21 (s, 1H), 496 (M − H) 7.50-7.45(m, 2H), 7.28-7.20 (m, 5H), 6.70-6.64 (m, 3H), 6.54 (d, 1H), 6.12 (s,1H), 3.82 (s, 3H), 3.68 (t, 4H), 3.24 (t, 4H), 2.33 (s, 3H) 96 ¹H NMR(400 MHz, CDCl₃) δ 8.21 (s, 2H), 7.52-7.42 (m, 540 (M − H) 2H), 7.30 (d,2H), 7.25-7.20 (m, 3H), 6.70-6.67 (m, 3H), 6.64 (d, 1H), 6.13 (s, 1H),4.40 (t, 2H), 3.74 (t, 2H), 3.67 (t, 4H), 3.33 (s, 3H), 3.23 (t, 4H),2.38 (s, 3H) 97 ¹H NMR (400 MHz, CDCl₃) δ 8.10 (s, 1H), 7.32-7.21 (m,580 (M + H) 5H), 7.06 (d, 2H), 6.82 (d, 2H), 6.38 (s, 1H), 6.31 (s, 1H),6.12 (s, 1H), 4.37 (t, 2H), 3.76 (t, 2H), 3.65 (t, 4H), 3.56-3.47 (m,1H), 3.22 (t, 4H), 2.38 (d, 6H), 2.23 (s, 3H), 1.10 (d, 6H) 98 ¹H NMR(400 MHz, CDCl₃) δ 8.50 (s, 1H), 7.48-7.46 (d, 600 (M + H) 1H),7.34-7.32 (m, 2H), 7.25-7.19 (m, 3H), 6.90 (d, 1H), 6.71-6.68 (dd, 1H),6.39 (s, 1H), 6.30 (s, 1H), 6.20 (s, 1H), 4.95 (s, 2H), 3.84 (s, 3H),3.64 (t, 4H), 3.22 (t, 4H), 2.37 (s, 3H), 2.31 (s, 3H), 2.23 (s, 3H) 99¹H NMR (400 MHz, CDCl₃) δ 8.03 (s, 1H), 7.90 (d, 1H), 387 (M − H)7.35-7.21 (m, 6H), 6.20 (d, 1H), 6.12 (s, 1H), 3.82 (s, 3H), 3.40 (t,4H), 2.33 (s, 3H), 2.00-1.97 (m, 4H) 100 ¹H NMR (400 MHz, CDCl₃) δ 8.57(broad s, 1H), 403 (M + H) 7.80-7.65 (m, 4H), 7.27 (t, 2H), 7.22-7.14(m, 4H), 6.15 (s, 1H), 3.85 (s, 3H), 2.35 (s, 3H) 101 ¹H NMR (400 MHz,CDCl₃) δ 8.32 (s, 1H), 7.46 (t, 1H), 422 (M + H) 7.29 (d, 2H), 7.25-7.16(m, 3H), 6.60 (d, 1H), 6.49 (d, 1H), 6.13 (s, 1H), 3.83 (t, 4H), 3.82(s, 3H), 3.08 (t, 4H), 2.33 (s, 3H) 102 ¹H NMR (400 MHz, CDCl₃) δ 8.56(d, 2H), 8.12 (s, 1H), 585 (M + H) 7.36-7.34 (m, 2H), 7.29-7.25 (m, 3H),7.05 (d, 2H), 6.96 (d, 2H), 6.82 (d, 2H), 6.38 (s, 1H), 6.30 (s, 1H),6.27 (s, 1H), 5.50 (s, 2H), 3.64 (t, 4H), 3.21 (t, 4H), 2.37 (s, 3H),2.25 (s, 3H), 2.22 (s, 3H) 103 ¹H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1H),7.51 (s, 1H), 623 (M + H) 7.32 (q, 2H), 7.22 (t, 3H), 7.06 (d, 2H), 6.84(d, 2H), 6.68 (d, 2H), 6.13 (s, 1H), 4.39 (t, 2H), 3.75-3.66 (m, 10H),3.40 (broad s, 3H), 3.32 (s, 3H), 3.22 (t, 4H), 2.38 (s, 6H) 104 ¹H NMR(400 MHz, CDCl₃) δ 8.27 (s, 1H), 7.58 (d, 2H), 514 (M − H) 7.01 (m, 3H),6.10 (s, 1H), 6.33 (s, 1H), 6.22 (d, 1H), 4.35 (t, 2H), 3.84 (t, 1H),3.70-3.63 (m, 6H), 3.30-3.27 (m, 6H), 2.38 (s, 3H), 2.31-2.26 (m, 2H),2.24 (s, 3H), 2.11-2.02 (m, 2H), 1.94-1.76 (m, 3H) 105 ¹H NMR (400 MHz,CDCl₃) δ 8.30 (s, 1H), 7.43 (t, 1H), 477 (M + H) 7.29 (d, 2H), 7.24-7.16(m, 3H), 6.62-6.58 (d, 1H), 6.49 (d, 1H), 6.12 (s, 1H), 3.82 (s, 3H),3.12 (t, 4H), 2.57 (t, 4H), 2.33 (s, 3H), 2.13 (s, 2H), 1.84-1.77 (m,1H), 0.91 (d, 6H) 106 ¹H NMR (400 MHz, CDCl₃) δ 8.28 (s, 1H), 7.41 (t,1H), 420 (M + H) 7.29-7.18 (m, 5H), 6.62-6.58 (dd, 1H), 6.51-6.48 (d,1H), 6.12 (s, 1H), 3.82 (s, 3H), 3.09 (t, 4H), 2.33 (s, 3H), 1.67-1.55(m, 6H) 107 ¹H NMR (400 MHz, CDCl₃) δ 8.22 (s, 1H), 7.55 (d, 2H), 530(M + H) 6.98 (d, 2H), 6.39 (s, 1H), 6.32 (s, 2H), 4.95 (dd, 2H), 4.84(s, 2H), 3.80 (s, 3H), 3.69-3.67 (m, 4H), 3.29-3.27 (m, 4H), 2.38 (s,3H), 2.34-2.26 (m, 2H), 2.24 (s, 3H), 2.11-2.01 (m, 2H), 1.95-1.78 (m,2H) 108 ¹H NMR (400 MHz, CDCl₃) δ 8.28 (s, 1H), 7.44 (t, 1H), 473 (M −H) 7.29-7.26 (m, 5H), 6.62-6.58 (d, 1H), 6.50-6.48 (d, 1H), 6.12 (s,1H), 4.89-4.87 (d, 2H), 3.82 (s, 3H), 3.12 (t, 4H), 2.90 (s, 2H), 2.50(t, 4H), 2.32 (s, 3H), 1.75 (s, 3H) 109 ¹H NMR (400 MHz, CDCl₃) δ 8.19(s, 1H), 7.41 (t, 1H), 517 (M − H) 7.30 (d, 2H), 7.23-7.17 (m, 3H),6.61-6.57 (dd, 1H), 6.49 (d, 1H), 6.12 (s, 1H), 4.88 (d, 2H), 4.40 (t,2H), 3.74 (t, 2H), 3.32 (s, 3H), 3.12 (t, 4H), 2.90 (s, 2H), 2.50 (t,4H), 2.38 (s, 3H), 1.76 (s, 3H) 110 ¹H NMR (400 MHz, CDCl₃) δ 8.02(broad s, 1H), 7.40 (t, 521 (M + H) 1H), 7.30 (d, 3H), 7.21 (d, 2H),6.59 (d, 1H), 6.49 (d, 1H), 6.13 (s, 1H), 4.39 (s, 2H), 3.74 (s, 2H),3.33 (s, 3H), 3.12 (s, 4H), 2.52 (s, 4H), 2.38 (s, 3H), 2.12 (s, 2H),1.80 (m, 1H), 0.91 (d, 6H) 111 ¹H NMR (400 MHz, CDCl₃) δ 8.19 (s, 1H),7.46 (1, 1H), 584 (M + H) 7.32 (m, 2H), 7.23-7.20 (m, 3H), 6.64 (d, 1H),6.54 (d, 1H), 6.39 (s, 1H), 6.30 (s, 1H), 6.20 (s, 1H), 4.94 (s, 2H),3.84 (s, 3H), 3.64 (t, 4H), 3.22 (t, 4H), 2.37 (s, 3H), 2.31 (s, 3H),2.23 (s, 3H) 112 ¹H NMR (400 MHz, CDCl₃) δ 8.28 (s, 1H), 7.43 (t, 1H),491 (M + H) 7.28 (d, 2H), 7.23-7.15 (m, 3H), 6.61-6.57 (dd, 1H), 6.48(d, 1H), 6.12 (s, 1H), 3.82 (s, 3H), 3.09 (t, 4H), 2.64 (t, 4H), 2.32(s, 3H), 2.10 (s, 2H), 0.88 (s, 9H) 113 ¹H NMR (400 MHz, CDCl₃) δ 8.18(s, 1H), 7.04 (t, 1H), 535 (M + H) 7.30 (d, 2H), 7.23-7.17 (m, 3H),6.60-6.56 (q, 1H), 6.47 (d, 1H), 6.12 (s, 1H), 4.39 (t, 2H), 3.74 (t,2H), 3.32 (s, 3H), 3.08 (t, 4H), 2.64 (t, 4H), 2.38 (s, 3H), 2.10 (s,2H), 0.88 (s, 9H) 114 ¹H NMR (400 MHz, CDCl₃) δ 8.18 (s, 1H), 7.38 (t,3H), 464 (M + H) 7.30 (d, 2H), 7.22-7.15 (m, 3H), 6.59 (dd, 1H), 6.49(d, 1H), 6.12 (s, 1H), 4.39 (t, 2H), 3.74 (t, 2H), 3.32 (s, 1H),3.01-3.07 (m, 4H), 2.38 (s, 3H), 1.66-1.65 (m, 5H), 1.57 (m, 1H) 115 ¹HNMR (400 MHz, CDCl₃) δ 8.20 (s, 1H), 7.27-7.20 (m, 420 (M + H) 5H), 6.95(d, 1H), 6.83-6.78 (m, 2H), 6.13 (s, 1H), 3.81 (s, 3H), 2.95 (t, 4H),2.33 (s, 3H), 1.73-1.69 (m, 4H), 1.56-1.55 (m, 2H) 116 ¹H NMR (400 MHz,CDCl₃) δ 8.23-8.20 (m, 2H), 7.50 (t, 496 (M − H) 1H), 7.28-7.23 (m, 5H),7.00 (d, 1H), 6.86-6.81 (m, 2H), 6.70-6.63 (m, 2H), 6.13 (s, 1H), 3.81(s, 3H), 3.69 (t, 4H), 3.13 (t, 4H), 2.33 (s, 3H) 117 ¹H NMR (400 MHz,CDCl₃) δ 8.21 (s, 1H), 7.44 (t, 1H), 466 (M + H) 7.30 (d, 2H), 7.23-7.17(m, 3H), 6.59 (dd, 1H), 6.48 (d, 1H), 6.13 (s, 1H), 4.40 (t, 2H),3.83-3.81 (m, 4H), 3.74 (t, 2H), 3.32 (s, 3H), 3.09-3.07 (m, 4H), 2.38(s, 3H) 118 ¹H NMR (400 MHz, CDCl₃) δ 8.19 (broad s, 1H), 477 (M + H)7.28-7.22 (m, 5H), 6.96 (d, 1H), 6.81 (t, 2H), 6.13 (s, 1H), 3.81 (s,3H), 3.04 (t, 4H), 2.55 (s, 4H), 2.33 (s, 3H), 2.13 (d, 2H), 1.83-1.77(m, 1H), 0.91 (d, 6H) 119 ¹H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1H),7.29-7.28 (d, 464 (M + H) 2H), 7.23 (d, 3H), 6.93-6.90 (d, 1H),6.80-6.78 (d, 2H), 6.13 (s, 1H), 4.39 (t, 2H), 3.72 (t, 2H), 3.32 (s,3H), 2.94 (t, 4H), 2.38 (s, 3H), 1.71 (m, 4H), 1.54 (m, 2H). 120 ¹H NMR(400 MHz, CDCl₃) δ 8.19 (s, 1H), 8.09 (d, 1H), 579 (M + H) 7.50 (t, 1H),7.29 (d, 2H), 7.23 (t, 3H), 7.10 (d, 2H), 6.84 (d, 2H), 6.68 (d, 1H),6.13 (s, 1H), 3.82 (s, 3H), 3.67 (t, 8H), 3.39 (s, 2H), 3.23 (t, 4H),2.43 (s, 4H), 2.33 (s, 3H) 121 ¹H NMR (400 MHz, CDCl₃) δ 8.33 (d, 1H),7.55 (d, 2H), 315 (M + H) 7.41-7.40 (d, 1H), 7.35 (t, 3H), 7.24-7.20 (m,1H), 4.55 (t, 2H), 3.68 (t, 2H), 3.3.6-3.31 (m, 5H), 1.63 (q, 2H), 0.98(t, 3H) 122 ¹H NMR (400 MHz, CDCl₃) δ 9.03 (s, 1H), 8.51 (s, 1H), 552(M + H) 7.61-7.55 (m, 4H), 7.34 (m, 4H), 7.07 (d, 2H), 6.38 (d, 2H),5.08 (s, 2H), 3.83 (s, 3H), 3.65 (m, 4H), 3.28 (m, 4H), 2.38 (s, 3H),2.32 (s, 3H) 123 ¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1H), 7.44 (t, 1H),568 (M − H) 7.30 (d, 2H), 7.25-7.18 (m, 3H), 6.64 (d, 1H), 6.54 (d, 1H),6.39 (s, 1H), 6.30 (s, 1H), 6.13 (s, 1H), 4.40 (t, 2H), 3.74 (t, 2H),3.65 (t, 4H), 3.33 (s, 3H), 3.22 (t, 4H), 2.38 (s, 3H), 2.37 (s, 3H),2.23 (s, 3H) 124 H NMR (400 MHz, CDCl₃) δ 8.12 (s, 1H), 7.31 (d, 2H),534 (M − H) 7.25-7.20 (m, 3H), 7.10 (d, 2H), 6.84 (d, 2H), 6.38 (s, 1H),6.30 (s, 1H), 6.14 (s, 1H), 3.82 (s, 3H), 3.65 (t, 4H), 3.22 (t, 4H),2.61 (t, 2H), 2.37 (s, 3H), 2.23 (s, 3H), 1.75 (m, 2H), 1.06 (t, 3H) 125H NMR (400 MHz, CDCl₃) δ 8.19 (s, 1H), 7.32 (d, 2H), 552 (M + H)7.29-7.21 (m, 3H, solvent overlap) 7.10-7.08 (d, 2H), 6.85-6.83 (d, 2H),6.38 (s, 1H), 6.31 (s, 1H), 6.23 (s, 1H), 5.6 (s, 2H), 3.65 (t, 4H),3.33 (s, 3H), 3.22 (t, 4H), 2.77 (q, 2H), 2.37 (s, 3H), 2.23 (s, 3H),1.54 (t, 3H) 126 ¹H NMR (400 MHz, CDCl₃) δ 8.12 (s, 1H), 7.30-7.21 (m,464 (M − H) 5H), 6.95 (d, 1H), 6.80 (d, 2H), 6.13 (s, 1H), 4.41 (t, 2H),3.84 (t, 4H), 3.72 (t, 2H), 3.32 (s, 3H), 3.01 (t, 4H), 2.38 (s, 3H 127H NMR (400 MHz, CDCl₃) δ 8.87 (s, 1H), 7.90 (d, 1H), 387 (M + H) 7.69(d, 1H), 7.49-7.34 (m, 5H), 7.29-7.22 (m, 3H, solvent overlap), 7.18 (t,1H), 6.16 (s, 1H), 3.86 (s, 3H), 2.36 (s, 3H) 128 ¹H NMR (400 MHz,CDCl₃) δ 8.44 (s, 1H), 7.36-7.32 (m, 404 (M + H) 3H), 7.25-7.15 (m, 3H),7.05 (d, 1H), 6.92 (d, 1H), 6.52 (d, 1H), 6.13 (s, 1H), 4.13-4.08 (q,2H), 3.84 (s, 3H), 2.33 (s, 3H), 1.43 (t, 3H). 129 ¹H NMR (400 MHz,CDCl₃) δ 8.20 (s, 1H), 7.31-7.29 (m, 552 (M + H) 2H), 7.25-7.20 (m, 3H),7.09 (d, 2H), 6.83 (d, 2H), 6.38 (s, 1H), 6.31 (s, 1H), 6.18 (s, 1H),3.83 (s, 3H), 3.69 (t, 2H), 3.65 (t, 4H), 3.39 (s, 3H), 3.22 (t, 4H),2.93 (t, 2H), 2.37 (s, 3H), 2.23 (s, 3H). 130 ¹H NMR (400 MHz, CDCl₃) δ8.21 (s, 1H), 7.29 (m, 3H), 536 (M − H) 7.23 (m, 2H), 7.11 (d, 2H), 6.80(d, 2H), 6.55 (s, 1H), 6.48 (s, 1H), 6.32 (s, 1H), 4.48 (s, 2H), 3.86(t, 7H), 3.40 (s, 3H), 3.29 (t, 4H), 2.60 (s, 3H), 2.37 (s, 3H) 131 ¹HNMR (400 MHz, CDCl₃) δ 8.26 (s, 1H), 7.33-7.26 (m, 568 (M + H) 5H), 7.14(d, 2H), 6.85 (d, 2H), 6.39 (d, 2H), 6.31 (s, 1H), 5.66 (s, 2H), 4.57(s, 2H), 3.65 (t, 4H), 3.41 (s, 3H), 3.31 (s, 3H), 3.23 (t, 4H), 2.37(s, 3H), 2.23 (s, 3H) 132 ¹H NMR (400 MHz, CDCl₃) δ 8.19 (s, 1H),7.32-7.30 (m, 552 (M + H) 3H), 7.25-7.24 (m, 2H), 7.10 (d, 2H), 6.85 (d,2H), 6.38 (s, 1H), 6.30 (s, 1H), 6.18 (s, 1H), 5.65 (s, 2H), 3.66-3.64(m, 4H), 3.56-3.55 (q, 2H), 3.23-3.21 (m, 4H), 2.42 (s, 3H), 2.37 (s,3H), 2.23 (s, 3H), 1.19 (t, 3H) 133 ¹H NMR (400 MHz, CDCl₃) δ 8.08 (s,1H), 7.31 (d, 3H), 568 (M + H) 7.22 (d, 2H), 7.06 (d, 2H), 6.82 (d, 2H),6.38 (s, 1H), 6.30 (s, 1H), 6.15 (s, 1H), 4.40 (t, 2H), 3.65 (t, 4H),3.22 (t, 4H), 2.89 (s, 2H), 2.39 (s, 3H), 2.37 (s, 3H), 2.23 (s, 3H),2.17 (s, 3H) 134 ¹H NMR (400 MHz, CDCl₃) δ 8.04 (s, 1H), 7.31-7.21 (m,614 (M + H) 7H), 7.06-7.04 (d, 2H), 6.93 (t, 1H), 6.88-6.81 (dd, 4H),6.38 (s, 1H), 6.30 (s, 1H), 6.14 (s, 1H), 4.60 (t, 2H), 4.39 (t, 2H),3.65 (t, 4H), 3.21 (t, 4H), 2.47 (s, 3H), 2.37 (s, 3H), 2.23 (s, 3H) 135¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1H), 7.33-7.31 (m, 580 (M + H) 2H),7.28-7.23 (m, 3H), 7.10 (d, 2H), 6.84 (d, 2H), 6.39 (s, 1H), 6.31 (s,1H), 6.18 (s, 1H), 5.64 (s, 2H), 3.65 (t, 4H), 3.49 (t, 2H), 3.22 (t,4H), 2.42 (s, 3H), 2.37 (s, 3H), 2.23 (s, 3H), 1.53 (q, 2H), 1.36-1.25(m, 2H), 0.87 (t, 3H) 136 ¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H),7.31-7.29 (m, 580 (M + H) 2H), 7.24-7.22 (m, 3H), 7.07 (d, 2H), 6.84 (d,2H), 6.38 (s, 1H), 6.30 (s, 1H), 6.11 (s, 1H), 4.33 (t, 2H), 3.66-3.64(m, 4H), 3.50-3.42 (m, 4H), 3.23-3.30 (m, 4H), 2.37 (s, 3H), 2.36 (s,3H), 2.23 (s, 3H), 2.05-2.02 (m, 2H), 1.20 (t, 3H) 137 ¹H NMR (400 MHz,CDCl₃) δ 8.17 (s, 1H), 7.32-7.22 (m, 552 (M − H) 5H), 7.09 (s, 2H), 6.84(d, 2H), 6.38 (s, 1H), 6.31 (s, 1H), 6.18 (s, 1H), 5.41 (s, 2H), 3.65(t, 4H), 3.22 (t, 4H), 2.42 (s, 3H), 2.37 (s, 3H), 2.23 (s, 3H), 2.13(s, 3H) 138 ¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1H), 7.32-7.30 (q, 582(M + H) 2H), 7.27-7.25 (m, 4H), 7.08 (d, 2H), 6.84 (d, 2H), 6.39 (s,1H), 6.31 (s, 1H), 6.19 (s, 1H), 5.72 (s, 2H), 3.68-3.64 (m, 5H), 3.50(t, 2H), 3.35 (s, 3H,) 3.22 (t, 4H), 2.44 (s, 3H), 2.37 (s, 3H), 2.23(s, 3H) 139 ¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1H), 7.33-7.31 (m, 566(M + H) 2H), 7.28-7.25 (m, 3H), 7.10 (d, 2H), 6.84 (d, 2H), 6.39 (s,1H), 6.31 (s, 1H), 6.19 (s, 1H), 5.65 (s, 2H), 3.65 (t, 4H), 3.45 (t,2H), 3.22 (t, 4H), 2.43 (s, 3H), 2.37 (s, 3H), 2.23 (s, 3H), 1.57 (m,2H), 0.88 (t, 3H) 140 ¹H NMR (400 MHz, CDCl₃) δ 8.12 (s, 1H), 7.32-7.25(m, 580 (M + H) 5H), 7.06 (d, 2H), 6.83 (d, 2H), 6.39 (s, 1H), 6.31 (s,1H), 6.13 (s, 1H), 4.39 (t, 2H), 3.77 (t, 2H), 3.64 (m, 4H), 3.36 (t,2H), 3.22 (m, 4H), 2.40 (s, 3H), 2.37 (s, 3H), 2.23 (s, 3H), 1.57-1.51(m, 2H), 0.87 (t, 3H) 141 ¹H NMR (400 MHz, CDCl₃) δ 8.20 (s, 1H),7.31-7.22 (m, 578 (M + H) 5H), 7.08 (d, 2H), 6.83 (d, 2H), 6.39 (s, 1H),6.31 (s, 1H), 6.14 (s, 1H), 5.73-5.64 (m, 2H), 4.95 (d, 2H), 4.08 (d,2H), 3.65 (m, 4H), 3.38 (s, 3H) 3.22 (m, 4H), 2.37 (s, 3H), 2.34 (s,3H), 2.23 (s, 3H) 142 ¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 7.31-7.21(m, 578 (M − H) 5H), 7.06 (d, 2H), 6.83 (d, 2H), 6.39 (s, 1H), 6.31 (s,1H), 6.12 (s, 1H), 4.22 (t, 2H), 3.65 (t, 4H), 3.42 (t, 2H), 3.34 (s,3H), 3.22 (t, 4H), 2.38 (s, 3H), 2.35 (s, 3H), 2.23 (s, 3H), 1.87-1.83(m, 2H), 1.70-1.65 (m, 2H). 143 ¹H NMR (400 MHz, DMSO-d₆) δ 10.17 (s,1H), 7.22 (m, 400 (M − H) 2H), 7.11 (m, 3H), 7.00 (d, 2H), 6.73 (d, 2H),6.09 (s, 1H), 3.81 (s, 3H), 3.02 (s, 4H), 2.31 (s, 3H), 1.58-1.49 (m,6H) 144 ¹H NMR (400 MHz, CDCl₃) δ 8.20 (s, 1H), 7.35-7.20 (m, 493 (M +H) 10H), 7.06 (d, 2H), 6.77 (d, 2H), 6.12 (s, 1H), 3.80 (s, 3H), 3.56(s, 2H), 3.13 (m, 4H), 2.59 (m, 4H), 2.32 (s, 3H) 145 ¹H NMR (400 MHz,CDCl₃) δ 8.21 (s, 1H), 7.31-7.21 (m, 471 (M − H) 5H), 7.09 (d, 2H), 6.79(d, 2H), 6.13 (s, 1H), 3.81 (s, 3H), 3.76 (t, 2H), 3.65 (t, 2H), 3.09(t, 4H), 2.82 (septet, 1H), 2.33 (s, 3H), 1.15 (d, 6H). 146 ¹H NMR (400MHz, CDCl₃) δ 8.13 (s, 1H), 7.44 (s, 1H), 587 (M − H) 7.32-7.29 (m, 2H),7.25-7.21 (m, 3H), 7.05 (d, 2H), 6.82 (d, 2H), 6.39 (s, 1H), 6.31 (s,1H), 6.16 (s, 1H), 5.34 (s, 2H), 3.65 (m, 4H), 3.22 (m, 4H), 2.48 (s,3H), 2.41 (s, 3H), 2.37 (s, 3H), 2.23 (s, 3H) 147 ¹H NMR (400 MHz,CDCl₃) δ 8.44 (s, 1H), 7.91 (d, 2H), 384 (M − H) 7.68 (s, 1H), 7.31-7.28(m, 4H), 7.26-7.21 (m, 4H), 6.15 (s, 1H), 3.83 (s, 3H), 2.34 (s, 3H) 148H NMR (400 MHz, CDCl₃) δ 8.44 (broad s, 1H), 7.90 (t, 402 (M − H) 1H),7.73 (s, 1H), 7.28-7.20 (m, 7H), 7.01 (d, 1H), 6.15 (s, 1H), 3.83 (s,3H), 2.34 (s, 3H) 149 ¹H NMR (400 MHz, CDCl₃) δ 8.30 (s, 1H), 7.91 (d,2H), 428 (M − H) 7.68 (s, 1H), 7.31-7.26 (m, 4H), 7.22-7.20 (m, 4H),6.15 (s, 1H), 4.41 (t, 2H), 3.74 (t, 2H), 3.33 (s, 3H), 2.39 (s, 3H) 150¹H NMR (400 MHz, CDCl₃) δ 8.18 (s, 1H), 7.31-7.18 (m, 473 (M + H) 5H),7.06 (d, 2H), 6.78 (d, 2H), 6.12 (s, 1H), 3.81 (s, 3H), 3.15-3.08 (m,4H), 2.73-2.68 (m, 2H), 2.55-2.52 (m, 2H), 2.32 (s, 3H), 2.17-2.14 (m,1H), 1.72-1.70 (m, 1H), 0.95 (d, 6H), 0.88 (d, 3H) 151 ¹H NMR (400 MHz,CDCl₃) δ 8.18 (s, 1H), 7.30-7.20 (m, 475 (M + H) 5H), 7.06 (d, 2H), 6.78(d, 2H), 6.12 (s, 1H), 3.81 (s, 3H), 3.51-3.47 (m, 1H), 3.35-3.31 (m,4H), 3.13 (t, 4H), 2.84-2.79 (m, 1H), 2.73 (t, 4H), 2.32 (s, 3H), 1.10(d, 3H) 152 ¹H NMR (400 MHz, CDCl₃) δ 8.17 (s, 1H), 7.30-7.22 (m, 511(M + H) 6H), 7.06 (d, 2H), 6.78 (d, 2H), 6.28 (s, 1H), 6.12 (s, 1H),6.04 (s, 1H), 3.81 (s, 3H), 3.13 (m, 4H), 2.98-2.94 (m, 2H), 2.72 (m,4H), 2.60-2.54 (m, 1H), 2.32 (s, 3H), 1.04 (d, 3H) 153 ¹H NMR (400 MHz,CDCl₃) δ 8.36 (s, 1H), 7.90 (d, 2H), 481 (M − H) 7.29-7.27 (m, 4H),7.23-7.21 (m, 3H), 6.99 (s, 1H), 6.15 (s, 1H), 3.84 (s, 3H), 3.62 (s,2H), 2.47 (m, 4H), 2.34 (s, 3H), 1.61 (m, 4H), 1.42 (m, 2H) 154 ¹H NMR(400 MHz, CDCl₃) δ 8.18 (s, 1H), 7.30-7.28 (m, 404 (M + H) 2H),7.24-7.20 (m, 3H), 7.09 (d, 2H), 6.77 (d, 2H), 6.12 (s, 1H), 3.83 (t,4H), 3.81 (s, 3H), 3.08 (t, 4H), 2.32 (s, 3H).

Activity Example Measurement of Minimum Inhibitory Concentrations (MICS)

Between 1 and 5 mgs of compound were accurately weighed out into asterile Eppendorf tube. The compound was dissolved in DMSO to give asolution containing 5 mg/mL. Tubes were stored at −20° C. untilrequired.

On the day of testing thawed solutions were vortex mixed to ensurehomogeneity. 30 μL of solution was removed and added to 570 μL ofsterile water in a separate sterile Eppendorf. The thoroughly mixedsolution was used to prepare a series of doubling dilutions in water, ina deep well plate. Thirteen replicate plates were prepared using aMinitrak by aspirating 20 μL from each well into eleven clearpolystyrene 96 well plates.

Spores of Aspergillus spp. (Aspergillus fumigatus [two strains],Aspergillus terreus [two strains], Aspergillus niger and Aspergillusflavus) were harvested from cultures grown on Sabarauds agar for 5 days,and resuspended in PBS/Tween 80 to approx 1×10⁷ cfu/mL. Each organismsuspension was diluted in YAG medium (1% glucose, 1% ammonium chlorideand 0.5% yeast extract) to 0.5−2×10⁴ cfu/mL. 80 μL of an organismsuspension was added to each well of the plate containing drugdilutions.

This produced MIC plates with a drug range 50-0.05 mg/L and organisminocula of 1−2×10⁴ cfu/mL for Aspergillus spp. All plates were incubatedfor 24 h at 35° C. Growth was assessed by monitoring the optical densityat 485 nm for each well. The MIC of a compound is the lowest drugconcentration that inhibits growth of an organism by >70% compared witha drug free control. MICs are recorded as mg/L. In cases where the MICof an organism is >=0.05 mg/L the MIC is repeated using a concentrationrange of 0.5-0.0005 mg/L.

Assays were also performed in RPMI medium for both Aspergillus spp.(strains described above) and Candida spp. (Candida albicans, Candidaglabrata, Candida krusei, Candida parapsilosis and Candida tropicalis).To perform MIC tests in this medium, dilutions of compounds are preparedin microtitre plates as described above. Fungal strains to be tested aregrown and harvested in an identical manner to that described above, andeach organism suspension was diluted in RPMI medium, containing 2%glucose and 0.135 M MOPS buffer (pH 7.0) to 0.5-2×10⁴ cfu/mL, ratherthan in YAG medium. 80 μL of an organism suspension was added to eachwell of the plate containing drug dilutions.

This produced MIC plates with a drug range 50-0.05 mg/L and organisminocula of 1−2×10⁴ cfu/mL. All plates were incubated for 24-48 h at 35°C. Growth was assessed by monitoring the optical density at 485 nm foreach well. The MIC of a compound is the lowest drug concentration thatinhibits growth of an organism by >80% compared with a drug freecontrol.

The following organisms were tested: Aspergillus flavus, Aspergillusfumigatus AF293 and AF210, Aspergillus niger, Aspergillus terreus AT4and AT49, Candida albicans, Candida glabrata, Candida krusei, Candidaparapsilosis and Candida tropicalis.

Other fungi including Absidia corymbifera; Acremonium spp; Alternariaalternata; Aspergillus nidulans; Aspergillus parasiticus; Bipolaris spp;Blastomyces dermatitidis; Blumeria graminis; Cladosporiumcladosporoides; Cladosporium herbarium; Coccidioides immitis;Coccidioides posadasii; Colletotrichium trifolii; Curvularia lunata;Colletotrichium trifolii; Cryptococcus neoformans; Encephalitozooncuniculi; Epicoccum nigrum; Epidermophyton floccosum; Exophiala spp;Exserohilum rostratum; Fusarium graminearium; Fusarium solani; Fusariumsporotrichoides; Histoplasma capsulatum; Leptosphaeria nodorum;Magnaporthe grisea; Microsporum canis; Mycosphaerella graminicola;Neurospora crassa; Paecilomyces lilanicus; Paecilomyces varioti;Penicillium chrysogenum; Phytophthora capsici; Phytophthora infestans;Plasmopara viticola; Pneumocystis jiroveci; Puccinia coronata; Pucciniagraminis; Pyricularia oryzae; Pythium ultimum; Rhizomucor sp.;Rhizoctonia solani; Rhizomucor spp.; Rhizopus spp.; Scedosporiumapiospermum; Scedosporium prolificans; Scopulariopsis brevicaulis;Trichophyton interdigitale; Trichophyton mentagrophytes; Trichophytonrubrum; Trichosporon asahii; Trichosporon beigelii; and Ustilago maydismay also be used in the above assay. Fungi are cultured by standardmethods known to those skilled in the art, and MICs determined as above.

Aspergillus MIC results in mg/L (YAG medium):

The following MIC results have been banded into grades. Thus, a grade of1 represents an MIC of greater than 10 mg/L. A grade of 2 represents anMIC of from 1 to 10 mg/L. A grade of 3 represents an MIC of less than 1mg/L.

Example A. A. A. fumigatus A. A. A. terreus no. flavus fumigatus 210niger terreus 49  1 3 3 3 3 3 3  2 3 2 2 1 3 3  3 2 1 2 1 3 3  4 2 2 2 21 2  5 2 3 3 2 3 3  6 3 3 3 3 3 3  7 3 3 3 3 3 3  8 2 3 3 3 2 2  9 3 3 33 3 3  10 2 1 1 1 1 2  11 3 3 3 3 3 3  12 3 3 3 3 3 3  13 3 3 3 3 3 3 14 3 3 3 3 3 3  15 3 3 3 3 3 3  16 3 3 3 3 3 3  17 2 2 2 2 2 2  18 3 33 1 3 3  19 2 1 1 1 1 2  20 1 1 3 1 3 3  21 3 3 3 3 3 3  22 3 3 3 3 3 3 23 3 3 2 3 3 3  24 3 3 3 3 3 3  25 2 3 3 2 2 2  26 1 3 3 3 3 3  27 1 33 2 2 2  28 2 3 3 3 3 3  29 1 1 1 1 1 1  30 2 2 2 1 2 2  31 3 2 2 2 3 3 32 3 2 2 2 3 3  33 1 1 1 1 1 2  34 3 3 3 3 3 3  35 3 3 3 3 3 3  36 3 33 3 3 3  37 3 3 3 3 3 3  38 3 3 3 3 3 3  39 3 3 3 3 3 3  40 3 3 3 3 3 3 41 a 3 3 3 3 3 3  41 b 1 2 2 1 1 1  42 1 2 2 1 1 1  43 3 2 2 1 2 2  443 3 3 3 3 3  45 3 3 3 3 3 3  46 3 2 3 1 1 3  47 3 3 3 2 2 3  48 1 2 3 11 1  49 3 2 2 1 1 3  50 3 3 3 3 3 3  51 3 3 3 3 3 3  52 3 3 3 3 3 3  533 3 3 3 3 3  54 2 3 3 2 2 3  55 1 2 2 1 1 2  56 1 2 2 2 2 2  57 2 3 3 22 3  58 2 2 2 1 2 2  59 1 2 2 1 2 2  60 1 2 2 2 2 2  61 1 1 2 1 1 1  623 3 3 3 3 3  63 3 3 3 2 3 3  64 3 3 3 3 3 3  65 1 1 1 1 1 1  66 2 3 2 12 3  67 3 3 3 2 3 3  68 1 2 1 1 2 2  69 2 3 3 3 3 3  70 2 3 3 1 3 3  711 1 1 1 1 2  72 2 3 3 3 3 3  73 1 3 3 3 1 2  74 1 3 3 3 2 2  75 1 1 1 11 1  76 1 2 2 1 1 1  77 1 3 3 2 2 2  78 1 1 1 1 1 2  79 3 2 2 2 3 3  801 1 1 1 1 1  81 1 1 1 1 1 1  82 1 2 2 1 2 2  83 1 2 2 1 2 2  84 1 1 1 11 1  85 1 1 1 2 1 1  86 2 1 1 1 1 1  87 1 3 3 3 2 3  88 1 3 3 2 2 1  891 3 3 2 2 2  90 3 3 3 3 3 3  91 1 2 2 1 1 2  92 3 3 3 3 3 3  93 2 3 3 32 2  94 2 3 3 2 3 3  95 3 3 3 3 3 3  96 3 3 3 3 3 3  97 2 2 3 2 2 2  981 3 3 3 3 3  99 3 2 3 2 3 3 100 3 3 2 3 3 3 101 3 3 3 3 3 3 102 1 2 1 11 1 103 1 3 3 1 2 2 104 1 2 2 1 2 2 105 3 3 3 3 3 3 106 3 3 3 3 3 3 1071 3 3 1 1 1 108 3 3 3 3 3 3 109 3 3 3 3 3 3 110 2 3 3 3 3 2 111 2 3 3 33 3 112 3 3 3 3 3 3 113 3 3 3 3 3 3 114 3 3 3 3 3 3 115 3 3 3 3 3 3 1163 3 3 3 3 3 117 3 3 2 3 3 3 118 3 3 3 3 3 3 119 2 3 3 3 3 3 120 3 3 3 33 3 121 1 1 2 1 2 2 122 1 3 2 2 1 1 123 3 3 3 3 3 3 124 3 3 3 3 3 3 1253 3 3 3 3 3 126 2 3 3 2 3 3 127 3 1 2 3 3 3 128 3 3 3 3 3 3 129 3 3 3 33 3 130 3 3 3 3 3 3 131 2 2 2 2 2 2 132 3 3 3 3 3 3 133 2 3 3 3 3 3 1342 2 1 1 2 2 135 1 3 2 2 2 1 136 3 3 3 3 2 3 137 3 3 3 3 3 3 138 2 3 3 33 3 139 2 3 3 3 2 3 140 2 2 3 2 2 2 141 2 3 3 2 2 2 142 3 3 3 3 3 3 1433 3 3 3 3 3 144 3 3 3 3 3 3 145 3 3 3 3 3 3 146 2 3 3 2 2 2 147 3 3 3 33 3 148 3 3 3 3 3 3 149 3 3 3 3 3 3 150 3 3 3 3 3 3 151 3 3 3 3 3 3 1523 3 3 3 3 3 153 3 3 2 3 2 3 154 3 3 3 3 3 3Aspergillus MIC Results in mg/L (RPMI Medium):

The following MIC results have been banded into grades as defined above.

Example A. A. A. fumigatus A. A. A. terreus no. flavus fumigatus 210niger terreus 49  1 3 3 3 3 3 3  2 1 1 1 1 1 1  3 1 1 1 1 2 2  4 1 1 1 11 1  5 2 2 2 2 3 3  6 3 3 3 3 3 3  7 3 3 3 3 3 3  8 1 2 2 2 2 2  9 1 3 33 2 2  10 1 1 1 1 1 1  11 3 3 3 3 3 3  12 3 3 3 3 3 3  13 3 3 3 3 3 3 14 3 3 3 3 3 3  15 3 3 3 3 3 3  16 3 3 2 3 3 3  17 1 1 1 1 1 1  18 2 33 1 3 3  19 1 1 1 1 1 1  20 1 1 1 1 1 2  21 3 3 3 3 3 3  22 3 3 3 3 3 3 23 3 2 2 2 3 3  24 2 3 3 3 2 1  25 1 1 2 2 1 1  26 1 3 3 3 1 1  27 1 22 2 1 1  28 2 3 3 3 2 2  29 1 1 1 1 1 1  30 1 1 1 1 1 1  31 2 2 2 2 3 3 32 2 1 1 2 2 2  33 1 1 1 1 1 1  34 3 3 3 3 3 3  35 3 3 3 3 3 3  36 3 33 3 3 3  37 3 2 2 2 3 3  38 3 3 3 3 3 3  39 3 3 3 3 3 3  40 3 3 3 3 3 3 41 a 1 2 1 1 2 3  41 b 1 2 1 1 1 1  42 1 2 1 1 1 1  43 2 1 1 1 2 1  443 3 3 3 3 3  45 3 3 3 3 3 3  46 1 1 1 1 2 2  47 2 2 2 2 2 2  48 1 1 1 11 1  49 2 2 1 1 2 2  50 3 3 3 3 3 3  51 3 3 3 3 3 3  52 2 3 3 3 3 3  533 3 3 3 3 3  54 1 3 2 2 1 1  55 1 1 1 1 1 1  56 1 1 1 1 1 1  57 1 2 2 22 2  58 1 1 1 1 1 1  59 1 2 2 1 1 1  60 1 2 2 2 1 1  61 1 1 2 1 1 1  623 3 3 3 3 3  63 3 3 3 3 3 3  64 2 3 3 3 2 3  65 1 1 1 1 1 1  66 1 2 2 12 2  67 2 2 2 1 3 3  68 1 1 1 1 1 1  69 1 3 3 3 2 2  70 2 2 2 1 2 2  711 1 1 1 1 1  72 2 2 2 2 2 2  73 1 3 3 3 1 1  74 1 3 3 3 2 2  75 1 1 1 11 1  76 1 1 2 1 1 1  77 1 2 2 1 1 1  78 1 1 1 1 1 1  79 2 1 1 2 2 2  801 1 1 1 1 1  81 1 1 1 1 1 1  82 1 1 1 1 1 1  83 1 1 1 1 1 1  84 1 1 1 11 1  85 1 1 1 2 2 2  86 1 1 1 1 1 1  87 1 3 3 3 2 2  88 1 3 3 2 1 1  891 2 2 2 1 1  90 3 3 3 3 3 3  91 1 1 1 1 1 1  92 1 3 3 3 1 1  93 1 2 2 21 1  94 1 3 2 2 2 2  95 3 3 3 3 3 3  96 2 3 3 3 3 2  97 2 3 2 2 2 2  982 3 3 3 3 3  99 3 3 2 3 3 3 100 3 3 2 3 3 3 101 3 3 3 3 3 3 102 1 1 1 11 1 103 1 2 2 3 2 2 104 1 1 1 1 1 1 105 3 3 3 3 3 3 106 3 3 3 3 3 3 1071 3 2 1 1 1 108 3 3 3 3 3 3 109 3 3 3 3 3 3 110 2 3 3 2 3 3 111 2 3 3 33 2 112 3 3 3 3 3 3 113 2 2 3 3 3 2 114 2 2 2 3 2 2 115 3 3 3 3 3 3 1161 3 3 3 3 3 117 1 2 2 3 2 1 118 3 3 3 3 3 3 119 2 3 3 3 3 2 120 3 3 3 33 3 121 1 1 1 1 1 1 122 1 1 1 2 1 1 123 3 3 3 3 3 2 124 2 2 2 1 2 2 1252 2 2 2 2 2 126 1 2 2 1 2 2 127 3 1 1 3 3 3 128 3 3 3 3 3 3 129 3 3 2 22 2 130 3 3 3 3 3 3 131 1 1 1 2 2 2 132 1 3 3 3 3 3 133 1 3 3 3 2 2 1341 1 1 1 1 1 135 1 1 1 1 1 1 136 2 2 2 2 2 2 137 2 3 2 2 2 2 138 2 3 3 22 2 139 1 2 2 2 2 2 140 1 1 1 1 1 1 141 1 1 1 1 1 1 142 3 3 3 3 3 3 1433 3 3 3 3 3 144 3 3 3 3 3 3 145 3 3 3 2 3 3 146 1 3 1 2 1 1 147 3 3 3 33 3 148 3 3 2 3 3 3 149 1 2 2 3 2 2 150 3 3 3 3 3 3 151 3 3 3 3 3 3 1523 3 3 3 3 3 153 2 2 2 3 3 3 154 3 3 3 3 3 3Candida MIC Results in mg/L (RPMI Medium):

The following MIC results have been banded into grades as defined above.

Example C. C. C. C. no. C. albicans glabrata krusei parapsilosistropicalis 9 2 3 3 3 2 13 3 3 3 3 3 47 2 3 2 2 2 52 2 3 3 2 2 57 2 3 3 22 59 3 3 2 3 3 60 3 3 3 3 2 63 2 3 3 3 3 68 3 3 2 3 3 69 2 3 2 3 3 70 23 2 3 2 72 3 3 2 3 3 73 2 3 2 2 3 74 2 3 2 3 3 76 3 3 3 3 3 81 3 3 3 3 384 3 3 3 3 3 85 2 2 2 2 2 86 3 3 3 3 3 87 2 3 2 3 3 88 2 3 3 3 3 89 2 33 3 3 103 3 3 3 3 3 104 2 3 2 3 3 109 3 3 3 3 2 113 3 3 3 3 3 114 3 3 33 3

In Vivo Testing Example

2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamidehas excellent activity in vitro against Aspergillus and otherfilamentous fungi and shows good oral bio-availability and tissuedistribution. The efficacy of oral dosed2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamidehas been tested in murine survival models of disseminated aspergillosis.

Methods: Temporary (TI) or persistently (PI) neutropenic CD-1 mousemodels of disseminated aspergillus were used. 3 days postimmunosuppression with cyclophosphamide (200 mg/kg ip) mice wereinfected IV with an LD₉₀ challenge of A. fumigatus A1163. Treatmentcommenced 5 h post infection and animals were treated for 9 days andobserved for either 2 days or 7 days following cessation of treatment.In PI models animals had a further dose of cyclophosphamide one dayafter infection.2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamidewas dosed orally as a suspension in HPMC/Tween 80 once or twice daily.Caspofungin dosed IP was used as a comparator.

Results: A dose dependent response was seen in the TI survival modelwith doses of 1.25 and 2.5 mg/kg per day showing little benefit, 5 mg/kgper day showing 80% survival, 10 mg/kg/day being highly effective (90%survival) and doses of 20, 30 and 40 mg/kg/day giving 100% survival. Ina severe PI model 20 mg/kg BD gave 70% survival at day 12, untreatedanimals were all dead at day 7. A comparison of once and twice dailydosing in a TI model with prolonged observation showed that 10 mg/kg BD(80% survival at day 18) was superior to 20 mg/kg OD (70% survival atday 18).Conclusions:2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamidedemonstrated dose dependent survival improvement following a lethal A.fumigatus infection and efficacy in persistently neutropenic models andin models where animals were observed for 7 days following cessation oftreatment.2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamidewas at least as effective as CAS in these models.

Combination Therapy Example 1 Determination of Combined Effect of TwoAntifungal Agents

In order to determine the combined effect of an antifungal pyrrolecompound and a second antifungal agent as described above a checkerboardtitration can be carried out. These are relatively simple tests todetermine if an additive or synergistic effect between two compounds ispresent. The description which follows describes an exemplarycheckerboard titration; the skilled person would readily identify whichaspects of the method can be changed, for example using differentorganisms, different growth media, different concentrations of stocksolutions and so forth.

In the checkerboard titration doubling dilutions of compound A (e.g. anantifungal pyrrole compound as defined earlier) are prepared in everyrow across a microtitre plate and doubling dilutions of compound B (e.g.a second antifungal agent as defined earlier) are prepared in everycolumn down a microtitre plate. The activity of the two compounds incombination can be compared with the activity of each compound alone. Insuch experiments a narrow range of dilutions can be tested for eachcompound around the minimum inhibitory concentration (MIC).

As an example, a stock solution of compound A (e.g. 5 mg/ml) can beprepared in a suitable solvent such as DMSO. A stock solution ofcompound B (e.g. caspofungin) is also prepared (e.g. 2 mg/ml). The stocksolution of compound A is diluted (e.g. at a concentration of 1:2000 inwater) to 2.5 μg/ml. From this stock, aqueous solutions containing thefollowing concentrations of compound A can be prepared: 0.9, 0.8, 0.7,0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, 0.025, 0.0125 μg/ml. 20 μl volumesof each stock solution can then be added to the first eleven wells in acolumn of a microtitre plate, with the remaining column being given 20μl of water. Each row of the plate contains 20 μl of a series ofdilutions of compound A and one free control well containing noantifungal agent.

The compound B stock solution can be diluted in water by adding 5.5 μlof stock solution to 10 ml water. From this stock aqueous dilutions ofcompound B containing the following concentrations can be prepared:0.55, 0.45, 0.35, 0.25, 0.15, 0.05, 0.025 ug/ml. Each of these stockscan then be added to every row in the microtitre plate containing thecompound A dilutions. The bottom row of the plate can be given 20 μl ofwater.

Thus each well contains 40 μl of liquid comprising 20 μl of compound Aor water and 20 μl of compound B or water.

Spores of a relevant organism (e.g. Aspergillus fumigatus AF210) areharvested, for example from a 5-10 day old culture grown on a Sabouradagar plates. A suspension is made in PBS/Tween80 and the number ofspores estimated using a spectrophotometer at A495 using a previouslyconstructed calibration curve.

Appropriate growth media can be used, for example RPMI or YAG media.These can be prepared in line with the following example: 10.1 g of RPMIpowder (Gibco) are added to a 1 L Duran bottle, along with 34.5 g MOPSbuffer and 18 g Glucose. Approximately 500 ml of deionised water isadded and the bottle placed on a magnetic stirrer to assist solution.When completely dissolved the solution is adjusted to pH 7.0 using 5NNaOH. The solution is then made up to 600 ml total volume usingdeionised water and then filter sterilised through a 0.2 μm membrane andstored at 4° C.

For the test the spores of the chosen organism are diluted in therelevant medium (e.g. RPMI) to give a concentration of 1−3×10⁴ cfu/ml.The media is vortex mixed and the 60 μl of spore suspension is added toeach well of the plate, to give a final spore concentration of0.5−2.5×10⁴ cfu/ml. The final concentrations of compound A and compoundB in the medium is:

Compound A: 0.18, 0.16, 0.14, 0.12, 0.1, 0.08, 0.06, 0.04, 0.03, 0.02,0.01 μg/ml

Compound B: 0.11, 0.09, 0.07, 0.05, 0.03, 0.01, 0.005 μg/ml

The plate is incubated in a moist chamber for 48 hrs and then examinedfor growth. The row containing dilutions of compound A without compoundB provides the MIC of compound A. Similarly, the column which containsdilutions of compound B with no compound A provides the MIC of compoundB.

To determine the combined effect of the compounds the Fractionalinhibitory concentration FIC is determined, where FIC is defined as:FIC=FIC_(A)+FIC_(B)=C_(A) ^(comb)/MIC_(A) ^(alone)+C_(B) ^(comb)/MIC_(B)^(alone)where MIC_(A) ^(alone) and MIC_(B) ^(alone) are the MICs of compounds Aand B when acting alone and C_(A) ^(comb) and C_(B) ^(comb) areconcentrations of compounds A and B at the isoeffective combinations,respectively. The interpretation of the FIC is as follows: a FIC valueof 0.5 reveals synergy, a value of 1 to 4 reveals indifference, and avalue of >4 represents antagonism.

In accordance with the description above, a study was carried out withAspergillus fumigatus AF210 in RPMI media with2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide(i.e. the compound of Example 1) as compound A and caspofungin ascompound B. In this experiment an FIC of 0.67 was obtained.

Combination Therapy Example 2 Determination of Synergy Between TwoAntifungal Compounds In Vivo

Antifungal drugs are often used in combination to treat systemicinfections in ill patients. When drugs are used together in combinationvarious interactions may occur, these actions may be synergistic,antagonistic or indifferent (also known as an additive effect). Forpatient care antagonistic combinations should be avoided as they may beassociated with a worse outcome, synergistic effects are desirablehowever indifferent or additive combinations can be of benefit.

Interactions between two antifungal drugs can be studied in vitro usingcheckerboard synergy tests, or kill curve type studies, however it isalso useful to be able to assess the interaction between a combinationof drugs in in vivo models which are more realistic as thepharmacokinetics effects of each drug are taken into account.

There are several models that can be used to assess the efficacy of acombination of antifungal drugs, the models typically being tissueburden models or survival models.

In the first model groups of mice (typically 6-7 although larger groupscan be used) are immunosuppressed with cyclophosphamide 200 mg/kg on day1, on day 4 they are then infected with the infecting organism egAspergilli. or Candida spp. Infection may be through the lateral tailvein, intranasal, pulmonary or GI. The inoculum is sufficient toestablish infection in different body organs. Four to 24 hours afterinfection animals are treated with each of the test drugs individuallyat appropriate doses and with both drugs in combination. Typical dosescould be from 5 to 150 mg/kg of the pyrrole agent in combination withthe approved dose of other marketed agents.

Different routes of administration may be used for the different drugs,and different frequencies of dosing may be appropriate for each drug.The animals are treated for up to 14 days and then remain untreated for12-18 hr following the last dose of drug.

A group of animals which are infected but untreated are used as controlsfor comparison purposes. The animals are then humanely euthanized, andthe kidneys are removed. Both kidneys from each mouse are pooled,weighed and then homogenised in 1 ml of PBS/Tween. The homogenate isthen diluted in PBS and aliquots of the homogenates are plated ontoSabourauds agar and incubated for 24-48 hrs. Colonies are counted andthe actual colony count per gram (cfu/gm) of tissue calculated takinginto account dilution factors and tissue weight.

The cfu/gm of each mouse in each treatment group is plotted graphically.This allows comparison of the untreated animals with the treatmentgroups, and also a comparison of each drug used singly and incombination. Statistical analyses can be carried out on each treatmentgroup compared with the control group and between the individual drugsand the combination of drugs.

Other in vivo studies that are used for assessing the efficacy ofcombinations in comparison with single drugs are survival studies. Inthese models groups of mice (typically 10 per group) areimmunosuppressed with cyclophosphamide and infected with A. fumigatus inthe same manner as the tissue burden study. Animals are treated withdrug for 10 days using relevant dosages, routes and frequencies and thenobserved for 2-7 days after treatment has ceased. The number of micesurviving in each group is assessed on a daily basis. Infected butuntreated animals serve as controls and usually succumb to infection anddie by day 5-7. The efficacy of compounds is assessed by comparingsurvival rates at the end of the study. Although such studies are usefulfor comparing different single agents unless individual agents have poorsurvival rates then it will be difficult to identify additive orsynergistic effects between two agents. More severe models can beemployed to reduce the survival rates for single agents such as using apersistently neutropenic survival model, in which animals are givenadditional doses of immunosuppressive agents or delayed treatment modelsin which the first dose of drug is given 24 hrs or later followinginfection.

The models described previously are disseminated models of A. fumigatusinfection in which infection is established in numerous body organsfollowing intravenous injection of spores. Alternative models ofinfection for conducting synergy studies include survival studies usingpulmonary models of infection. In such models Aspergillus spores areintroduced into the lung either through inhalation of aerosols or sporesuspensions. Infection develops in the lung, the most common site ofinfection in humans. These infections are perhaps a better mimic ofhuman infection. Such infection models can be used to examine synergybetween compounds. These models are typically severe as the animals arepersistently immunosuppressed and untreated animals rapidly succumb toinfection. Further modifications to these models can be made by delayingtreatment and continuing observation of animals following cessation oftreatment.

Synergy studies are carried out by comparing the effect of eachindividual drug and the drugs in combination. If drugs are highly potentand give good survival rates when used singly despite increasing theseverity of the infection then a suitable approach is to lower the doseof each drug either by reducing the dose or dosing frequency. In thisway survival rates below 50% may be achieved which will allow synergy tobe demonstrated when both drugs are used in combination.

In another example of combination therapy, dosing of the novel pyrroleagent may allow the reduced dosing of other more toxic antifungalagents. This would result in a reduction of the toxic effects ordrug-drug interaction profiles ordinarily seen with the establishedagent.

Examples of this would be with the azole class of antifungals wheretoxicities and drug interactions are well known. By using members ofthis class, specifically itraconazole, voriconazole and posaconazole, incombination with the novel pyrrole agent described , increased efficacycould be expected with reduced azole dosing and result in reducedtoxicities.

The invention claimed is:
 1. A pharmaceutical combination comprising acombination of a first antifungal agent which is a pyrrole derivative offormula (I) or a pharmaceutically acceptable salt thereof, with a secondantifungal agent:

wherein: R1 represents hydrogen, unsubstituted or substituted C1-C8alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —COR′ or —SO₂(C1-C4 alkyl), or agroup -A2, -L2-A2, -L3-A2, -A2-L3-A3 or -A4; A1 represents a C3-C6cycloalkyl or an unsubstituted or substituted C6-C10 aryl or 5- to12-membered heterocyclyl group; A2 and A3 are the same or different andrepresent C3-C6 cycloalkyl or an unsubstituted or substituted C6-C10aryl or 5- to 12-membered heterocyclyl group; A4 is an unsubstituted orsubstituted 5- to 12-membered heterocyclyl group wherein 1 or 2 ringcarbon atoms are replaced with a group selected from >C(═O),>S(═O)₂, >C(═NOR7), >C═CH₂ or >C(—OCH₂CH₂O—), where R7 is hydrogen or aC1-C4 alkyl group; L1 represents a bond, a C1-C6 alkylene group in whichnone, one, two or three —CH₂— groups are independently replaced by —O—,—S— or —NR′—, or a 5- to 12-membered heterocyclyl group; L2 represents—NR′—, —O—, —CO—, —OCO, —OCONR′R″—, —CONR′R″— or —SO₂—; L3 represents abond or a C1-C4 alkylene group in which none, one or two —CH₂— groupsare independently replaced by —O—, —S— or —NR′—; n is 1 or 2; R6represents hydrogen or C1-C4 alkyl; R5 represents an unsubstituted orsubstituted group selected from C6-C10 aryl, a 5- to 12-memberedheterocyclyl group, C1-C8 alkyl and C3-C6 cycloalkyl, halogen or a groupof formula —B1-B2 or —B3; B1 represents an unsubstituted or substitutedC6-C10 aryl group; B2 represents an unsubstituted or substituted C6-C10aryl or 5- to 12-membered heterocyclyl group; B3 is an unsubstituted orsubstituted 5- to 12-membered heterocyclyl group where 1 or 2 ringcarbon atoms are replaced with a group selected from >C(═O),>S(═O)₂, >C(═NOR11), >C═CH₂ or >C(—OCH₂CH₂O—), where R11 is hydrogen ora C1-C4 alkyl group; R2 and R3 independently represent C6-C10 aryl, a 5-to 12-membered heterocyclyl group, C3-C6 cycloalkyl, hydrogen, halogen,C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, —OR′, —SR′,—SOR′, —SO₂R′, —SO₂NR′R″, —SO₃H, —NR′R″, —NR′COR′, —CO₂R′, —CONR′R″,—COR′, —OCOR′, —CF₃, —NSO₂R′ or —OCONR′R″, or a group (C1-4) alkyl-A5,wherein none, one or two —CH₂— groups are independently replaced by —O—,—S— or —NR′— and wherein A5 represents C6-10 aryl or a 5- to 12-memberedheterocyclyl group; or R2 and R3 together with the ring atoms to whichthey are bonded form a 5- to 7-membered, saturated or partiallysaturated ring containing a nitrogen atom from the adjacent pyrrolering, and optionally one or two further heteroatoms selected from N, Oand S, with the proviso that R2 and R3 do not form, together with thepyrrole ring to which they are bonded, a tetrahydroindolizine ring; R4represents hydrogen, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl,—OR′, —CONR′R″, —COR′, —CN, —NO₂, —NR′R″, CF₃, —Y—Z, C6-C10 aryl, or 5-to 12-membered heterocyclyl group, or a group of formula -Alk⁶-L5-A12,where Alk⁶ is a C1-C4 alkylene group, L5 is a group of formula—O—C(═O)—, —C(═O)— or —NR13-C(═O)— and R13 is hydrogen or C1-C4 alkyl,and A12 is an unsubstituted or substituted C6-C10 aryl or 5- to12-membered heterocyclyl group; Y represents C1-C8 alkylene, C2-C8alkenylene or C2-C8 alkynylene; Z represents halogen, C3-C6 cycloalkyl,—OR′, —SR′, —SOR′, —SO₂R′, —SO₂NR′R″, —SO₃H, —NR′R″, —NR′COR′, —NO₂,—CO₂R′, —CONR′R″, —COR′, —OCOR′, —CN, —CF₃, —NSO₂R′, —OCONR′R″ or—CR′═NOR″; and R′ and R″ independently represent hydrogen, C1-C8 alkyl,C2-C8 alkenyl or C2-C8 alkynyl; wherein an alkyl, alkenyl, alkynyl,cycloalkyl, aryl or heterocyclyl group or moiety can be substituted orunsubstituted; and wherein: a substituted alkyl, alkenyl or alkynylgroup or moiety is a said alkyl, alkenyl or alkynyl group or moietywhich is substituted with up to three substituents selected fromhalogen, hydroxy, amino, (C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, C1-C4alkoxy, —S(C1-C4 alkyl), —CO₂H, —CO₂(C1-C4 alkyl), phenyl, 5- or6-membered heterocyclyl, CONR^(b)′R^(b)″ and NR^(b)′CO(C1-C4 alkyl)where R^(b)′ and R^(b)″ are the same or different and represent hydrogenor unsubstituted C1-C4 alkyl, wherein the substitutents on a substitutedalkyl, alkenyl or alkynyl group or moiety are themselves unsubstitutedor, the case of C1-C4 alkoxy substituents, may be further substitutedwith unsubstituted methoxy or ethoxy; a substituted cycloalkyl group isa said cycloalkyl group which is substituted with up to threesubstituents selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Zand —Y—Z; a substituted aryl or heterocyclyl group or moiety is a saidaryl or heterocyclyl group or moiety which is substituted with up tothree substituents selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8alkynyl, Z and —Y—Z.
 2. A combination according to claim 1, wherein thepyrrole derivative of formula (I) or pharmaceutically acceptable saltthereof and the second antifungal agent are formulated for simultaneousor successive administration.
 3. A combination according to claim 1,wherein the second antifungal agent is selected from the groupconsisting of azoles, polyenes, purine nucleotide inhibitors, pyrimidinenucleotide inhibitors, mannan inhibitors, protein elongation factorinhibitors, echinocandins, allylamines, anti-HSP90 antibodies,bactericidal/permeability inducing protein products or polyoxins, or oneof the compounds AN2690, AN2718 or icofungipen.
 4. A combinationaccording to claim 3, wherein the second antifungal agent is (i) anazole selected from clotrimazole, econazole, bifonazole, butoconazole,fenticonazole, fluconazole, isoconazole, itraconazole, ketoconazole,miconazole, oxiconazole, sertaconazole, sulconazole, tioconazole,isavuconazole, ravuconazole, posaconazole, terconazole and voriconazole;(ii) an echinocandin selected from anidulafungin, caspofungin andmicafungin; (iii) an allylamine selected from terbinafine, butenafine,amorolfine and naftifine; (iv) a polyene selected from amphotericin Band nystatin; (v) a purine or pyrimidine nucleotide inhibitor which isflucytosine; (vi) a mannan inhibitor which is pradamicin; (vii) aprotein elongation factor inhibitor selected from sordarin and analoguesthereof; or (viii) a polyoxin which is nikkomycin Z.
 5. A pharmaceuticalcomposition comprising (i) a first antifungal agent which is a pyrrolederivative of formula (I) or a pharmaceutically acceptable salt thereof,(ii) a second antifungal agent, and (iii) a pharmaceutically acceptablecarrier or diluent:

wherein: R1 represents hydrogen, unsubstituted or substituted C1-C8alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —COR′ or —SO₂(C1-C4 alkyl), or agroup -A2, -L2-A2, -L3-A2, -A2-L3-A3 or -A4; A1 represents a C3-C6cycloalkyl or an unsubstituted or substituted C6-C10 aryl or 5- to12-membered heterocyclyl group; A2 and A3 are the same or different andrepresent C3-C6 cycloalkyl or an unsubstituted or substituted C6-C10aryl or 5- to 12-membered heterocyclyl group; A4 is an unsubstituted orsubstituted 5- to 12-membered heterocyclyl group wherein 1 or 2 ringcarbon atoms are replaced with a group selected from >C(═O),>S(═O)₂, >C(═NOR7), >C═CH₂ or >C(—OCH₂CH₂O—), where R7 is hydrogen or aC1-C4 alkyl group; L1 represents a bond, a C1-C6 alkylene group in whichnone, one, two or three —CH₂— groups are independently replaced by —O—,—S— or —NR′—, or a 5- to 12-membered heterocyclyl group; L2 represents—NR′—, —O—, —CO—, —OCO—, —OCONR′R″—, —CONR′R″— or —SO₂—; L3 represents abond or a C1-C4 alkylene group in which none, one or two —CH₂— groupsare independently replaced by —O—, —S— or —NR′—; n is 1 or 2; R6represents hydrogen or C1-C4 alkyl; R5 represents an unsubstituted orsubstituted group selected from C6-C10 aryl, a 5- to 12-memberedheterocyclyl group, C1-C8 alkyl and C3-C6 cycloalkyl, halogen or a groupof formula —B1-B2 or —B3; B1 represents an unsubstituted or substitutedC6-C10 aryl group; B2 represents an unsubstituted or substituted C6-C10aryl or 5- to 12-membered heterocyclyl group; B3 is an unsubstituted orsubstituted 5- to 12-membered heterocyclyl group where 1 or 2 ringcarbon atoms are replaced with a group selected from >C(═O),>S(═O)₂, >C(═NOR11), >C═CH₂ or >C(—OCH₂CH₂O—), where R11 is hydrogen ora C1-C4 alkyl group; R2 and R3 independently represent C6-C10 aryl, a 5-to 12-membered heterocyclyl group, C3-C6 cycloalkyl, hydrogen, halogen,C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, —OR′, —SR′,—SOR′, —SO₂R′, —SO₂NR′R″, —SO₃H, —NR′R″, —NR′COR′, —CO₂R′, —CONR′R″,—COR′, —OCOR′, —CF₃, —NSO₂R′ or —OCONR′R″, or a group (C1-4) alkyl-A5,wherein none, one or two —CH₂— groups are independently replaced by —O—,—S— or —NR'- and wherein AS represents C₆₋₁₀ aryl or a 5- to 12-memberedheterocyclyl group; or R2 and R3 together with the ring atoms to whichthey are bonded form a 5- to 7-membered, saturated or partiallysaturated ring containing a nitrogen atom from the adjacent pyrrolering, and optionally one or two further heteroatoms selected from N, Oand S, with the proviso that R2 and R3 do not form, together with thepyrrole ring to which they are bonded, tetrahydroindolizine ring; R4represents hydrogen, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl,—OR′, —CONR′R″, —COR′, —CN, —NO₂, —NR′R″, CF₃, —Y—Z, C6-C10 aryl, or 5-to 12-membered heterocyclyl group, or a group of formula -Alk⁶-L5-A12,where Alk⁶ is a C1-C4 alkylene group, L5 is a group of formula—O—C(═O)—, —C(═O)— or —NR13—C(═O)— and R13 is hydrogen or C1-C4 alkyl,and A12 is an unsubstituted or substituted C6-C10 aryl or 5- to12-membered heterocyclyl group; Y represents C1-C8 alkylene, C2-C8alkenylene or C2-C8 alkynylene; Z represents halogen, C3-C6 cycloalkyl,—OR′, —SR′, —SOR′, —SO₂R′, —SO₂NR′R″, —SO₃H, —NR′R″, —NR′COR′, —NO₂,—CO₂R′, —CONR′R″, —COR′, —OCOR′, —CN, —CF₃, —NSO₂R′, —OCONR′R″ or—CR′═NOR″; and R′ and R″ independently represent hydrogen, C1-C8 alkyl,C2-C8 alkenyl or C2-C8 alkynyl; wherein an alkyl, alkenyl, alkynyl,cycloalkyl, aryl or heterocyclyl group or moiety can be substituted orunsubstituted; and wherein: a substituted alkyl, alkenyl or alkynylgroup or moiety is a said alkyl, alkenyl or alkynyl group or moietywhich is substituted with up to three substituents selected fromhalogen, hydroxy, amino, (C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, C1-C4alkoxy, —S(C1-C4 alkyl), —CO₂H, —CO₂(C1-C4 alkyl), phenyl, 5- or6-membered heterocyclyl, CONR^(b)′R^(b)″ and NR^(b)′CO(C1-C4 alkyl)where R^(b)′ and R^(b)″ are the same or different and represent hydrogenor unsubstituted C1-C4 alkyl, wherein the substitutents on a substitutedalkyl, alkenyl or alkynyl group or moiety are themselves unsubstitutedor, the case of C1-C4 alkoxy substituents, may be further substitutedwith unsubstituted methoxy or ethoxy; a substituted cycloalkyl group isa said cycloalkyl group which is substituted with up to threesubstituents selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Zand —Y—Z; a substituted aryl or heterocyclyl group or moiety is a saidaryl or heterocyclyl group or moiety which is substituted with up tothree substituents selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8alkynyl, Z and —Y—Z.
 6. A kit comprising, in admixture or in separatecontainers, a first antifungal agent which is a pyrrole derivative offormula (I) or a pharmaceutically acceptable salt thereof and a secondantifungal agent:

wherein: R1 represents hydrogen, unsubstituted or substituted C1-C8alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —COR′ or —SO₂(C1-C4 alkyl), or agroup -A2, -L2-A2, -L3-A2, -A2-L3-A3 or -A4; A1 represents a C3-C6cycloalkyl or an unsubstituted or substituted C6-C10 aryl or 5- to12-membered heterocyclyl group; A2 and A3 are the same or different andrepresent C3-C6 cycloalkyl or an unsubstituted or substituted C6-C10aryl or 5- to 12-membered heterocyclyl group; A4 is an unsubstituted orsubstituted 5- to 12-membered heterocyclyl group wherein 1 or 2 ringcarbon atoms are replaced with a group selected from >C(═O),>S(═O)₂, >C(═NOR7), >C═CH₂ or >C(—OCH₂CH₂O—), where R7 is hydrogen or aC1-C4 alkyl group; L1 represents a bond, a C1-C6 alkylene group in whichnone, one, two or three —CH₂— groups are independently replaced by —O—,—S— or —NR′—, or a 5- to 12-membered heterocyclyl group; L2 represents—NR′—, —O—, —CO—, —OCO—, —OCONR′R″—, —CONR′R″— or —SO₂—; L3 represents abond or a C1-C4 alkylene group in which none, one or two —CH₂— groupsare independently replaced by —O—, —S— or —NR′—; n is 1 or 2; R6represents hydrogen or C1-C4 alkyl; R5 represents an unsubstituted orsubstituted group selected from C6-C10 aryl, a 5- to 12-memberedheterocyclyl group, C1-C8 alkyl and C3-C6 cycloalkyl, halogen or a groupof formula —B1-B2 or —B3; B1 represents an unsubstituted or substitutedC6-C10 aryl group; B2 represents an unsubstituted or substituted C6-C10aryl or 5- to 12-membered heterocyclyl group; B3 is an unsubstituted orsubstituted 5- to 12-membered heterocyclyl group where 1 or 2 ringcarbon atoms are replaced with a group selected from >C(═O),>S(═O)₂, >C(═NOR11), >C═CH₂ or >C(—OCH₂CH₂O—), where R11 is hydrogen ora C1-C4 alkyl group; R2 and R3 independently represent C6-C10 aryl, a 5-to 12-membered heterocyclyl group, C3-C6 cycloalkyl, hydrogen, halogen,C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, —OR′, —SR′,—SOR′, —SO₂R′, —SO₂NR′R″, —SO₃H, —NR′R″, —NR′COR′, —CO₂R′, —CONR′R″,—COR′, —OCOR′, —CF₃, —NSO₂R′ or —OCONR′R″, or a group (C1-4) alkyl-A5,wherein none, one or two —CH₂— groups are independently replaced by —O—,—S— or —NR′— and wherein A5 represents C6-10 aryl or a 5- to 12-memberedheterocyclyl group; or R2 and R3 together with the ring atoms to whichthey are bonded form a 5- to 7-membered, saturated or partiallysaturated ring containing a nitrogen atom from the adjacent pyrrolering, and optionally one or two further heteroatoms selected from N, Oand S, with the proviso that R2 and R3 do not form, together with thepyrrole ring to which they are bonded, a tetrahydroindolizine ring; R4represents hydrogen, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl,—OR′, —CONR′R″, —COR′, —CN, —NO₂, —NR′R″, CF₃, —Y—Z, C6-C10 aryl, or 5-to 12-membered heterocyclyl group, or a group of formula -Alk⁶-L5-A12,where Alk⁶ is a C1-C4 alkylene group, L5 is a group of formula—O—C(═O)—, —C(═O)— or —NR13—C(═O)— and R13 is hydrogen or C1-C4 alkyl,and A12 is an unsubstituted or substituted C6-C10 aryl or 5- to12-membered heterocyclyl group; Y represents C1-C8 alkylene, C2-C8alkenylene or C2-C8 alkynylene; Z represents halogen, C3-C6 cycloalkyl,—OR′, —SR′, —SOR′, —SO₂R′, —SO₂NR′R″, —SO₃H, —NR′R″, —NR′COR′, —NO₂,—CO₂R′, —CONR′R″, —COR′, —OCOR′, —CN, —CF₃, —NSO₂R′, —OCONR′R″ or—CR′═NOR″; and R′ and R″ independently represent hydrogen, C1-C8 alkyl,C2-C8 alkenyl or C2-C8 alkynyl; wherein an alkyl, alkenyl, alkynyl,cycloalkyl, aryl or heterocyclyl group or moiety can be substituted orunsubstituted; and wherein: a substituted alkyl, alkenyl or alkynylgroup or moiety is a said alkyl, alkenyl or alkynyl group or moietywhich is substituted with up to three substituents selected fromhalogen, hydroxy, amino, (C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, C1-C4alkoxy, —S(C1-C4 alkyl), —CO₂H, —CO₂(C1-C4 alkyl), phenyl, 5- or6-membered heterocyclyl, CONR^(b)′R^(b)″ and NR^(b)′CO(C1-C4 alkyl)where R^(b)′ and R^(b)″ are the same or different and represent hydrogenor unsubstituted C1-C4 alkyl, wherein the substitutents on a substitutedalkyl, alkenyl or alkynyl group or moiety are themselves unsubstitutedor, the case of C1-C4 alkoxy substituents, may be further substitutedwith unsubstituted methoxy or ethoxy; a substituted cycloalkyl group isa said cycloalkyl group which is substituted with up to threesubstituents selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Zand —Y—Z; a substituted aryl or heterocyclyl group or moiety is a saidaryl or heterocyclyl group or moiety which is substituted with up tothree substituents selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8alkynyl, Z and —Y—Z.
 7. A compound which is a pyrrole derivative offormula (I) or a pharmaceutically or agriculturally acceptable saltthereof:

wherein R1 represents hydrogen, unsubstituted or substituted C1-C8alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —COR′ or —SO₂(C1-C4 alkyl), or agroup -A2, -L2-A2, -L3-A2, -A2-L3-A3 or -A4; A2 and A3 are the same ordifferent and represent C3-C6 cycloalkyl or an unsubstituted orsubstituted C6-C10 aryl or 5- to 12-membered heterocyclyl group; A4 isan unsubstituted or substituted 5- to 12-membered heterocyclyl groupwherein 1 or 2 ring carbon atoms are replaced with a group selectedfrom >C(═O), >S(═O)₂, >C(═NOR7), >C═CH₂ or >C(OCH₂CH₂O), where R7 ishydrogen or a C1-C4 alkyl group; L1 represents a bond, a C1-C6 alkylenegroup in which none, one, two or three —CH₂— groups are independentlyreplaced by —O—, —S— or —NR′—, or a 5- to 12-membered heterocyclylgroup; L2 represents —NR′—, —O—, —CO—, —OCO—, —OCONR′R″—, —CONR′R″— or—SO₂—; L3 represents a bond or a C1-C4 alkylene group in which none, oneor two —CH₂— groups are independently replaced by —O—, —S— or —NR′—; nis 1 or 2; R5 represents an unsubstituted or substituted group selectedfrom C6-C10 aryl, a 5- to 12-membered heterocyclyl group, C1-C8 alkyland C3-C6 cycloalkyl, halogen or a group of formula B1 B2 or —B3; B1represents an unsubstituted or substituted C6-C10 aryl group; B2represents an unsubstituted or substituted C6-C10 aryl or 5- to12-membered heterocyclyl group; B3 is an unsubstituted or substituted 5-to 12-membered heterocyclyl group where 1 or 2 ring carbon atoms arereplaced with a group selected from >C(═O), >S(═O)₂, >C(═NOR11), >C═CH₂or >C(OCH₂CH₂O), where R11 is hydrogen or a C1-C4 alkyl group; R3represents C6-C10 aryl, a 5- to 12-membered heterocyclyl group, C3-C6cycloalkyl, hydrogen, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8alkynyl, C3-C6 cycloalkyl, —OR′, —SR′, —SOR′, —SO₂R′, —SO₂NR′R″, —SO₃H,—NR′R″, —NR′COR′, —CO₂R′, —CONR′R″, —COR′, —OCOR′, —CF₃, —NSO₂R′ or—OCONR′R″, or a group (C1-4) alkyl-A5, wherein none, one or two —CH₂—groups are independently replaced by —O—, —S— or —NR′— and wherein ASrepresents C6-10 aryl or a 5- to 12-membered heterocyclyl group; A1 is aC3-C6 cycloalkyl or an unsubstituted or substituted C6-C10 aryl, 5- or6-membered heterocyclyl or 8- to 10-membered bicyclic heterocyclylgroup; R6 represents hydrogen; R2 represents C6-C10 aryl, a 5- to12-membered heterocyclyl group other than benzothiophene, unsubstitutedC3-C6 cycloalkyl, hydrogen, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8alkynyl, C3-C6 cycloalkyl, —OR′, —SR′, —SOR′, —SO₂R′, —SO₂NR′R″, —SO₃H,—NR′R″, —NR′COR′, —CO₂R′, —CONR′R″, —COR′, —OCOR′, —CF₃, —NSO₂R′ or—OCONR′R″, or a group (C1-4) alkyl-A5, wherein none, one or two —CH₂—groups are independently replaced by —O—, —S— or —NR′— and wherein A5represents C6-10 aryl or a 5- to 12-membered heterocyclyl group; or R2together with R3 and the ring atoms to which they are bonded form a 5-to 7-membered, saturated or partially saturated ring containing anitrogen atom from the adjacent pyrrole ring, and optionally one or twofurther heteroatoms selected from N, O and S, with the proviso that R2and R3 do not form, together with the pyrrole ring to which they arebonded, a tetrahydroindolizine ring; wherein when R2 represents aryl orheterocyclyl it is unsubstituted or substituted with one or moreunsubstituted substituents selected from halogen, —NR^(a)′R^(a)″,—CO₂R^(a)′, —CONR^(a)′R^(a)″, —OCONR^(a)″R^(a)″, —OCOR^(a)′, —COCF₃ andhydroxyl, or C1-C6 alkyl or C1-C4 alkoxy which are unsubstituted orsubstituted with a hydroxyl or unsubstituted C1-C4 alkoxy group; whereinR^(a)′ and R^(a)″ are independently selected from hydrogen,unsubstituted C1-C4 alkyl and C1-C4 alkyl substituted with a hydroxyl orunsubstituted C1-C4 alkoxy group R4 represents hydrogen, halogen, C1-C8alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —OR′, —CONR′R″, —CN, —NO₂, —NR′R″,CF₃, —Y—Z, C6-C10 aryl, or 5- to 12-membered heterocyclyl group, or agroup of formula -Alk⁶-L5-A12, where Alk⁶ is a C1-C4 alkylene group, L5is a group of formula —O—C(═O)—, —C(═O)— or —NR13—C(═O)— and R13 ishydrogen or C1-C4 alkyl, and A12 is an unsubstituted or substitutedC6-C10 aryl or 5- to 12-membered heterocyclyl group; Y represents C1-C8alkylene, C2-C8 alkenylene or C2-C8 alkynylene; Z represents halogen,C3-C6 cycloalkyl, —OR′, —SR′, —SOR′, —SO₂R′, —SO₂NR′R″, —SO₃H, —NR′R″,—NR′COR′, —NO₂, —CO₂R′, —CONR′R″, —COR′, —OCOR′, —CN, —CF₃, —NSO₂R′,—OCONR′R″ or —CR′═NOR″; and R′ and R″ independently represent hydrogen,C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl; wherein an alkyl, alkenyl,alkynyl, cycloalkyl, aryl or heterocyclyl group or moiety can besubstituted or unsubstituted; and wherein: a substituted alkyl, alkenylor alkynyl group or moiety is a said alkyl, alkenyl or alkynyl group ormoiety which is substituted with up to three substituents selected fromhalogen, hydroxy, amino, (C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, C1-C4alkoxy, —S(C1-C4 alkyl), —CO₂H, —CO₂(C1-C4 alkyl), phenyl, 5- or6-membered heterocyclyl, CONR^(b)′R^(b)″ and NR^(b)′CO(C1-C4 alkyl)where R^(b)′ and R^(b)″ are the same or different and represent hydrogenor unsubstituted C1-C4 alkyl, wherein the substitutents on a substitutedalkyl, alkenyl or alkynyl group or moiety are themselves unsubstitutedor, the case of C1-C4 alkoxy substituents, may be further substitutedwith unsubstituted methoxy or ethoxy; a substituted cycloalkyl group isa said cycloalkyl group which is substituted with up to threesubstituents selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Zand —Y—Z; a substituted aryl or heterocyclyl group or moiety on A1 toA5, A12, R3, the ring formed by R2 and R3, R4, R5, L1, or B1 to B3, is asaid aryl or heterocyclyl group or moiety which is substituted with upto three substituents selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8alkynyl, Z and —Y—Z.
 8. A compound according to claim 7, wherein R2represents phenyl, hydrogen, —COO(C1-C4 alkyl), halogen, unsubstitutedC3-C6 cycloalkyl, or a C1-C4 alkyl, C2-C4 alkenyl or C1-C4 alkoxy groupwhich is unsubstituted or substituted with —SMe, —SEt, hydroxyl,di(C1-C4 alkyl)amino, —COO(C1-C4 alkyl), —CONR′R″, —NR′CO(C1-C4 alkyl),unsubstituted C1-C4 alkoxy or C1-C4 alkoxy substituted with —OMe or—OEt, where R′ and R″ are the same or different and represent hydrogenor unsubstituted C1-C4 alkyl; or R2 represents a group (C1-C4) alkyl-A5,wherein none or one —CH₂— groups are independently replaced by —O—, —S—or —NR′— and wherein A5 represents phenyl, pyridinyl or oxazolyl.
 9. Acompound which is a pyrrole derivative of formula (IB) or apharmaceutically or agriculturally acceptable salt thereof:

wherein: R1 represents hydrogen, unsubstituted or substituted C1-C8alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —COR′ or —SO₂(C1-C4 alkyl), or agroup -A2, -L2-A2, -L3-A2, -A2-L3-A3 or -A4; A1 represents a C3-C6cycloalkyl or an unsubstituted or substituted C6-C10 aryl or 5- to12-membered heterocyclyl group; A2 and A3 are the same or different andrepresent C3-C6 cycloalkyl or an unsubstituted or substituted C6-C10aryl or 5- to 12-membered heterocyclyl group; A4 is an unsubstituted orsubstituted 5- to 12-membered heterocyclyl group wherein 1 or 2 ringcarbon atoms are replaced with a group selected from >C(═O),>S(═O)₂, >C(═NOR7), >C═CH₂ or >C(—OCH₂CH₂O—), where R7 is hydrogen or aC1-C4 alkyl group; L1 represents a bond, a C1-C6 alkylene group in whichnone, one, two or three —CH₂— groups are independently replaced by —O—,—S— or —NR′—, or a 5- to 12-membered heterocyclyl group; L2 represents—NR′—, —O—, —CO—, —OCO—, —OCONR′R″—, —CONR′R″— or —SO₂—; L3 represents abond or a C1-C4 alkylene group in which none, one or two —CH₂— groupsare independently replaced by —O—, —S— or —NR′—; n is 1 or 2; R⁶represents hydrogen or C1-C4 alkyl; R5 represents an unsubstituted orsubstituted group selected from C6-C10 aryl, a 5- to 12-memberedheterocyclyl group, C1-C8 alkyl and C3-C6 cycloalkyl, halogen or a groupof formula —B1-B2 or —B3; B1 represents an unsubstituted or substitutedC6-C10 aryl group; B2 represents an unsubstituted or substituted C6-C10aryl or 5- to 12-membered heterocyclyl group; B3 is an unsubstituted orsubstituted 5- to 12-membered heterocyclyl group where 1 or 2 ringcarbon atoms are replaced with a group selected from >C(═O),>S(═O)₂, >C(═NOR11), >C═CH₂ or >C(—OCH₂CH₂O—), where R11 is hydrogen ora C1-C4 alkyl group; R² is a group of formula -Alk₁-X—R^(a)′, whereinAlk₁ is an unsubstituted or substituted C1-C6 alkylene group, X is agroup —O—, —S—, NR^(a)″—, —CO₂—, —CONR^(a)″—, —OCO—, —OCONR^(a)″— or—SO₂—, and R^(a)′ and R^(a)″ are independently selected from hydrogenand unsubstituted or substituted C1-C4 alkyl; R³ represents C6-C10 aryl,a 5- to 12-membered heterocyclyl group, C3-C6 cycloalkyl, hydrogen,halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl,—OR′, —SR′, —SOR′, —SOX, —SO₂NR′R″, —SO₃H, —NR′R″, —NR′COR′, —CO₂R′,—CONR′R″, —COR′, —OCOR′, —CF₃, —NSO₂R′ or —OCONR′R″, or a group (C1-4)alkyl-A5, wherein none, one or two —CH₂— groups are independentlyreplaced by —O—, —S— or —NR′— and wherein AS represents C6-10 aryl or a5- to 12-membered heterocyclyl group; R4 represents hydrogen, halogen,C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —OR′, —CONR′R″, —COR′, —CN,—NO₂, —NR′R″, CF₃, —Y—Z, C6-C10 aryl, or 5- to 12-membered heterocyclylgroup, or a group of formula -Alk⁶-L5-A12, where Alk⁶ is a C1-C4alkylene group, L5 is a group of formula —O—C(═O)—, —C(═O)— or—NR13—C(═O)— and R13 is hydrogen or C1-C4 alkyl, and A12 is anunsubstituted or substituted C6-C10 aryl or 5- to 12-memberedheterocyclyl group; Y represents C1-C8 alkylene, C2-C8 alkenylene orC2-C8 alkynylene; Z represents halogen, C3-C6 cycloalkyl, —OR′, —SR′,—SOR′, —SO₂R′, —SO₂NR′R″, —SO₃H, —NR′R″, —NR′COR′, —NO₂, —CO₂R′,—CONR′R″, —COR′, —OCOR′, —CN, —CF₃, —NSO₂R′, —OCONR′R″ or —CR′═NOR″; andR′ and R″ independently represent hydrogen, C1-C8 alkyl, C2-C8 alkenylor C2-C8 alkynyl; wherein an alkyl, alkenyl, alkynyl, cycloalkyl, arylor heterocyclyl group or moiety can be substituted or unsubstituted; andwherein: a substituted alkyl, alkenyl or alkynyl group or moiety is asaid alkyl, alkenyl or alkynyl group or moiety which is substituted withup to three substituents selected from halogen, hydroxy, amino, (C1-C4alkyl)amino, di(C1-C4 alkyl)amino, C1-C4 alkoxy, —S(C1-C4 alkyl), —CO₂H,—CO₂(C1-C4 alkyl), phenyl, 5- or 6-membered heterocyclyl,CONR^(b)′R^(b)″ and NR^(b)′CO(C1-C4 alkyl) where R^(b)′ and R^(b)″ arethe same or different and represent hydrogen or unsubstituted C1-C4alkyl, wherein the substitutents on a substituted alkyl, alkenyl oralkynyl group or moiety are themselves unsubstituted or, the case ofC1-C4 alkoxy substituents, may be further substituted with unsubstitutedmethoxy or ethoxy; a substituted cycloalkyl group is a said cycloalkylgroup which is substituted with up to three substituents selected fromC1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Z and —Y—Z; a substitutedaryl or heterocyclyl group or moiety is a said aryl or heterocyclylgroup or moiety which is substituted with up to three substituentsselected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Z and —Y—Z;wherein the compound is not3-[2-(4-fluoro-phenylaminooxalyl)-pyrrol-1-yl]-propionic acid or3-{2-[2-(3,4-Dimethoxy-phenyl)-ethylaminooxalyl]-pyrrol-1-yl}-propionicacid.
 10. A composition comprising a compound or pharmaceuticallyacceptable salt as defined in claim 7 and a pharmaceutically acceptablecarrier or diluent, or comprising a compound or agriculturallyacceptable salt as defined in claim 7 and an agriculturally acceptablecarrier or diluent.
 11. A compound according to claim 7, wherein L1represents a bond, a 5- to 7-membered heterocyclyl group or a C1-C6alkylene group wherein none, one or two —CH2— groups are independentlyreplaced by —O— or —NR′—, wherein R′ is hydrogen, unsubstituted C1-C4alkyl or C1-C4 alkyl substituted with an unsubstituted C1-C4 alkoxygroup; and A1 represents a phenyl, napthyl, a 5- or 6-memberedheterocyclyl group or an 8-10-membered bicyclic heterocyclyl group. 12.A compound according to claim 7, wherein n is 1; R1 is hydrogen, anunsubstituted group selected from C1-6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, —CO(C1-C4 alkyl) and —SO2(C1-C4 alkyl), or a group -A2, -L2-A2,-L3-A2, -A2-L3-A3 or A4; A2 and A3 are the same or different andrepresent phenyl or a 5- or 6-membered heterocyclic group; and L3represents a bond or a C1-C4 alkylene group in which none, one or two—CH2— moieties are independently replaced with —O— or —NR′—, wherein R′represents hydrogen or unsubstituted C1-C4 alkyl.
 13. A compoundaccording to claim 7, wherein R5 is phenyl, a monocyclic 5- to8-membered heterocyclyl ring, an unsubstituted C3-C6 cycloalkyl group,an unsubstituted C1-C8 alkyl or a C1-C8 alkyl substituted with a C1-C4alkoxy group.
 14. A compound which is a pyrrole derivative of formula(IA) or a pharmaceutically acceptable salt thereof:

wherein: A1 represents phenyl, naphthyl, pyridyl, piperidinyl,benzofuranyl, isoquinolinyl or quinolinyl, each of which may beunsubstituted or substituted with one or more substituents selected fromunsubstituted C1-C4 alkyl, C1-C4 alkyl substituted with an unsubstitutedC1-C4 alkoxy group, unsubstituted C1-C4 alkoxy, —CO₂H and halogen, orfrom a group of formula —(C1-C2 alkyl)-O—(C1-C4 alkyl)-NR′R″ where R′and R″ are the same or different and represent hydrogen or C1-C4 alkyl,or R′ and R″, together with the nitrogen atom to which they are bonded,form a piperazinyl or morpholinyl group which is unsubstituted orsubstituted with 1 or 2 C1-C4 alkyl groups; n represents one or two; L1represents a bond, a saturated 5- to 7-membered heterocyclyl groupcontaining one or two nitrogen atoms, or an unsubstituted C1-C6 alkylenegroup wherein none, one or two —CH₂— groups are independently replacedwith —O— or —NR′—, wherein R′ is hydrogen, unsubstituted C1-C4 alkyl orC1-C4 alkyl substituted with an unsubstituted C1-C4 alkoxy group, andwherein the heterocyclyl group is unsubstituted or substituted with anunsubstituted group selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy andhalogen; when L1 is a bond, R1 represents hydrogen, -A2, —SO₂-A2,A2-L3-A3 or A4; and when L1 is other than a bond, R1 represents hydrogenor an unsubstituted group selected from C1-C6 alkyl, C2-C6 alkenyl,C2-C6 alkynyl and —SO₂(C1-C4 alkyl), or a group -A2, —SO₂-A2, -L3-A2 or-A2-L3-A3; A2 and A3 independently represent phenyl or a 5- or6-membered heterocyclyl group, wherein A2 and A3 are unsubstituted orsubstituted with one, two or three substituents selected from theunsubstituted substituents halogen, —COCF₃, —OCONR′R″ and —NR′R″, andfrom C1-C4 alkyl and C1-C4 alkoxy groups which are unsubstituted orsubstituted with —OH, —OMe, —OEt or —O(C1-C4 alkyl)-O(C1-C2 alkyl),wherein R′ and R″ are independently selected from hydrogen,unsubstituted C1-C4 alkyl and C1-C4 alkyl substituted with a hydroxyl orunsubstituted C1-C4 alkoxy group; L3 represents a bond or unsubstitutedmethylene or ethylene; A4 represents unsubstituted dioxothiomorpholinyl,methoxyiminopiperidinyl, methoxyiminopyrrolidinyl, methylenepiperidinyl,dioxoazaspirodecyl or oxadihydropyrazolyl; R5 represents unsubstitutedor substituted phenyl, unsubstituted C3-C6 cycloalkyl, unsubstituted orsubstituted pyridinyl or piperidinyl, or unsubstituted thiophenyl,furanyl or tetrahydropyranyl, the substituents being selected fromhalogen, unsubstituted C1-C4 alkyl, unsubstituted C1-C4 alkoxy or R5 isa C1-C8 alkyl group substituted with a C1-C4 alkoxy group; and either(i) R2 represents unsubstituted phenyl, hydrogen, halogen, unsubstitutedC1-C4 alkoxy, unsubstituted C2-C4 alkenyl, unsubstituted C1-C4 alkyl, orC1-C4 alkyl or C2-C4 alkenyl substituted with —OMe, —OEt, —OPr, —OBu,—OCH₂CH₂OMe, —SMe, hydroxy, di(C1-C4 alkyl)amino, —COO(C1-C4 alkyl),—CONR′R″ or —NR′CO(C1-C4 alkyl) where R′ and R″ are the same ordifferent and represent hydrogen or unsubstituted C1-C4 alkyl; or R2represents a group (C1-C4) alkyl-A5, wherein none or one —CH₂— groupsare independently replaced by —O— and wherein A5 represents phenyl,pyridinyl or oxazolyl, each of which is unsubstituted or substitutedwith one or two substituents selected from halogen, C1-C4 alkyl andC1-C4 alkoxy; and R3 represents hydrogen, halogen, unsubstituted phenyl,unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 alkyl, or C1-C4 alkylsubstituted with —OMe or —OEt; or (ii) R2 and R3 together with the ringatoms to which they are bonded form a substituted or unsubstitutedsaturated or partially saturated 5- or 6-membered ring containing anitrogen atom from the adjacent pyrrole ring and none or one furtherheteroatom selected from N and O, with the proviso that R2 and R3 do notform, together with the pyrrole ring to which they are bound, atetrahydroindolizine ring, the substituents being selected fromunsubstituted C1-C4 alkyl and unsubstituted C1-C4 alkoxy groups.
 15. Acompound according to claim 14, wherein A1 represents phenyl, which maybe unsubstituted or substituted with one or more substituents selectedfrom unsubstituted C1-C4 alkyl, C1-C4 alkyl substituted with anunsubstituted C1-C4 alkoxy group, unsubstituted C1-C4 alkoxy, —CO₂H andhalogen; n represents one; L1 represents an unsubstituted, saturated 5-to 7-membered heterocyclyl group containing two nitrogen atoms, theheterocycle being attached to A1 and to R1 via a nitrogen atom; R1represents unsubstituted C1-C6 alkyl, unsubstituted C2-C6 alkenyl, or agroup -A2, —CH₂-A2 or -A2-CH₂-A3; A2 and A3 independently representphenyl or a 5- or 6-membered heterocyclyl group, wherein A2 and A3 areunsubstituted or substituted with one, two or three substituentsselected from the unsubstituted substituents halogen, —COCF₃, —OCONR′R″and —NR′R″, and from C1-C4 alkyl and C1-C4 alkoxy groups which areunsubstituted or substituted with —OH, —OMe, —OEt or —O(C1-C4alkyl)-O(C1-C2 alkyl), wherein R′ and R″ are independently selected fromhydrogen, unsubstituted C1-C4 alkyl and C1-C4 alkyl substituted with ahydroxyl or unsubstituted C1-C4 alkoxy group; R5 representsunsubstituted phenyl; R2 represents hydrogen, or C1-C4 alkyl or C2-C4alkenyl, each of which may be unsubstituted or substituted with —OMe,—OEt, —OPr, —OBu, —OCH₂CH₂OMe, —SMe, hydroxy, di(C1-C4 alkyl)amino,—COO(C1-C4 alkyl), —CONR′R″ or —NR′CO(C1-C4 alkyl) where R′ and R″ arethe same or different and represent hydrogen or unsubstituted C1-C4alkyl; or R2 represents a group (C1-C4) alkyl-A5, wherein none or one—CH₂— groups are independently replaced by —O— and wherein A5 representsphenyl, pyridinyl or oxazolyl, each of which is unsubstituted orsubstituted with one or two substituents selected from halogen, C1-C4alkyl and C1-C4 alkoxy; and R3 represents hydrogen or C1-C4 alkyl whichis unsubstituted or substituted with —OMe or —OEt.
 16. A compoundaccording to claim 15, wherein A1 is unsubstituted phenyl and L1 ispiperazinyl.
 17. A compound according to claim 7, wherein the pyrrolederivative is2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(1-phenyl-1H-pyrrol-2-yl)-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-1-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-1H-pyrrol-2-yl)-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(2-methyl-7-phenyl-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-6-yl)-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(2-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl)-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(7-phenyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-isopropyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-3-(3-morpholin-4-yl-propoxymethyl)-phenyl]-2-oxo-acetamide,N-{3-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(3-furan-2-yl-1,5-dimethyl-1H-pyrrol-2-yl)-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1,5-dimethyl-3-thiophen-2-yl-1H-pyrrol-2-yl)-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(3-isopropyl-1,5-dimethyl-1H-pyrrol-2-yl)-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1,5-dimethyl-3-(tetrahydro-pyran-4-yl)-1H-pyrrol-2-yl]-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-naphthalen-1-yl-2-oxo-acetamide,N-{3-(2-Dimethylamino-ethoxymethyl)-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,2-(1,4-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-3-[3-(4-methyl-piperazin-1-yl)-propoxymethyl]-phenyl}-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-isopropyl-1-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,N-{2-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-3-hydroxy-phenyl}-2-oxo-acetamide,N-(2,3-Dihydro-benzofuran-4-yl)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,N-{3-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[3-isopropyl-1-(2-methoxy-ethyl)-5-methyl-1H-pyrrol-2-yl]-2-oxo-acetamide,N-{2-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-ethoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(3-methoxy-propyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,2-[1-(2-Methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-N-quinolin-5-yl-acetamide,N-Isoquinolin-5-yl-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-quinolin-8-yl-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-quinolin-5-yl-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-pyridin-4-yl-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-ethyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-3-phenyl-1-propyl-1H-pyrrol-2-yl)-2-oxo-acetamide,2-(1-Butyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-quinolin-3-yl-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-[4-(4-pyridin-2-yl-piperazin-1-yl)-phenyl]-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(6-methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4-methyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(2-phenyl-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepin-3-yl)-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(1-phenyl-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepin-3-yl)-acetamide,N-Isoquinolin-8-yl-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-isoquinolin-8-yl-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-naphthalen-2-yl-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-methyl-4-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,2-(1-Benzyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[5-(4-methyl-piperazin-1-yl)-naphthalen-1-yl]-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-3-methyl-phenyl}-2-oxo-acetamide,(2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-5-methyl-3-phenyl-pyrrol-1-yl)-aceticacid methyl ester,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-ethyl-1-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[5-ethyl-1-(2-methoxy-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-5-methyl-3-phenyl-pyrrole-1-carboxylicacid ethyl ester,2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-5-methyl-3-phenyl-pyrrole-1-carboxylicacid methyl ester,2-[3-(2-Chloro-phenyl)-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,2-[4-(2-Chloro-phenyl)-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,2-[3-(4-Chloro-phenyl)-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,2-[1-(2-Methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-N-phenyl-1-acetamide,(2-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-pyrrol-1-yl)-aceticacid methyl ester,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-methoxymethyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-methoxymethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-hydroxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,2-[1-(2-Acetylamino-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-hydroxy-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazine-1-yl]-phenyl}-2[1-(2-methoxy-ethyl)-3-thiophen-2-yl-1H-pyrol-2-yl]-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)piperazin-1-yl]-phenyl}-2-[3-isobutyl-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-2-oxo-acetamide,2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-5-methyl-3-phenyl-pyrrol-1-yl)-aceticacid ethyl ester,2-[3-(3-Chloro-phenyl)-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,2-[4-(3-Chloro-phenyl)-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazine-1-yl]-phenyl}-2[1-(2-methoxy-ethyl)-3-thiophen-3-yl-1H-pyrol-2-yl]-2-oxo-acetamide,(2-{4-[4-(4,6-Dimethylpyridine-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-3-phenylpyrrol-1-yl)acetic acid ester,(2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-3-phenyl-pyrrol-1-yl)-aceticacid methyl ester,2-(1-Carbamoylmethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-methylcarbamoylmethyl-3-phenyl-1-H-pyrrol-2-yl)-2-oxo-acetamide,2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-5-methyl-3-phenyl-pyrrol-1-yl)aceticacid isopropyl ester,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[5-isopropyl-1-(2-methoxy-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-2-oxo-quinolin-5-yl-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[3-(2-methoxy-ethyl)-5-methyl-1-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,2-[1-(2-Methoxy-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-N-phenyl-1-acetamide,2-[1-(2-Methoxy-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-N-propyl-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[3-isopropyl-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-2-oxoacetamide,2-[1-(2-Dimethylamino-ethyl)-3-phenyl-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,2-[1-(2-Dimethylamino-ethyl)-4-phenyl-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,2-[1-(2-Dimethylamino-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,(2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-3-thiophen-2-yl-pyrrol-1-yl)-aceticacid methyl ester,(2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-[3-isopropyl-pyrrol-1-yl)-aceticacid methyl ester,(2-{4-[4-(4,6-Dimethylpyridine-2-yl)piperazine-1-yl]-phenylaminooxalyl}-3-isobutyl-pyrrol-1-yl)-aceticacid methyl ester,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(4-fluoro-1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-3-phenyl-1pyridin-2-ylmethyl-1H-pyrrol-2-yl)-2-oxo-acetamide,N-{2-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-3-phenyl-1-pyridin-3-ylmethyl-1H-pyrrol-2-yl)-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[4-fluoro-1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[2-fluoro-4-(4-pyridin-2-yl-piperazin-1-yl)-phenyl]-2-oxo-acetamide,N-[2-Fluoro-4-(4-pyridin-2-yl-piperazin-1-yl)-phenyl]-2-[1-(2-methoxy-ethyl-)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-isopropoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,(2-{2-Chloro-4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-5-methyl-3-phenyl-pyrrol-1-yl)-aceticacid methyl ester,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-(6-pyrrolidin-1-yl-pyridin-3-yl)-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(2-fluoro-4-oxazole-2-yl-phenyl)-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(2-fluoro-4-morpholin-4-yl-phenyl)-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-3-phenyl-1-pyridin-4-ylmethyl-1H-pyrrol-2-yl)-2-oxo-acetamide,2-[1-(2-Methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrrol-2-yl]-N-{4-[4-(5-morpholin-4-ylmethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,2-[3-Cyclobutyl-1-(2-methoxy-ethyl)-1H-pyrrol-2-yl]-N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperizin-1-yl]-phenyl}-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[2-fluoro-4-(4-isobutyl-piperazin-1-yl)-phenyl]-2-oxoacetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(2-fluoro-4-piperidin-1-yl-phenyl)-2-oxo-acetamide,(3-Cyclobutyl-2-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl-]-phenylaminooxalyl}-pyrrol-1-yl)-aceticacid methyl ester,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{2-fluoro-4-[4-(2-methyl-allyl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,N-{2-Fluoro-4-[4-(2-methyl-allyl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,N-[2-Fluoro-5-(4-isobutyl-piperazine-1-yl)-phenyl]-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,(2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-2-fluoro-phenylaminooxylyl}-5-methyl-3-phenyl-pyrrol-1-yl)-aceticacid methyl ester,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(2,2-dimethyl-propyl)-piperazin-1-yl]-2-fluoro-phenyl}-2-oxo-acetamide,N-{4-[4-(2,2-Dimethyl-propyl)-piperazin-1-yl]-2-fluoro-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,N-(2-Fluoro-4-piperidin-1-yl-phenyl)-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-fluoro-4-piperidin-1-yl-phenyl)-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[3-fluoro-4-(4-pyridin-2-yl-piperazin-1-yl)-phenyl]-2-oxo-acetamide,N-(2-Fluoro-4-morpholin-4-yl-phenyl)-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[3-fluoro-4(4-isobutyl-piperazin-1-yl)-phenyl]-2-oxo-acetamide,N-(3-Fluoro-4-piperidin-1-yl-phenyl)-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(5-morpholin-4-ylmethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,2-[1-(2-Methoxy-ethyl)-4-phenyl-1H-pyrrol-2-yl]-2-oxo-N-propyl-acetamide,(2-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylaminooxalyl}-4-phenyl-pyrrol-1-yl)-aceticacid methyl ester,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-2-fluoro-phenyl}-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperizin-1-yl]-phenyl}-2-[1-methyl-3-phenyl-5-propyl-1H-pyrrol-2-yl)-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-ethyl-1-methoxymethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,N-(3-Fluoro-4-morpholin-4-yl-phenyl)-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(5-fluoro-naphthalen-1-yl)-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(1-ethyl-4-fluoro-1H-indol-5-yl)-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[5-(2-methoxy-ethyl)-1-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methoxymethyl-1-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,2-(1,5-Bis-methoxymethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazine-1-yl]-phenyl}-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(1-ethoxymethyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[5-methyl-1-(2-methylsulfanyl-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[5-methyl-1-(2-phenoxy-ethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,2-(1-Butoxymethyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(3-ethoxy-propyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-1-methylsulfanylmethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethoxymethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-(5-methyl-3-phenyl-1-propoxymethyl-1H-pyrrol-2-yl)-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[5-methyl-3-phenyl-1-(2-propoxy-ethyl)-1H-pyrrol-2-yl]-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(4-methoxy-but-2-enyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[1-(4-methoxy-butyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-(4-piperidin-1-yl-phenyl)-acetamide,N-[4-(4-Benzyl-piperazin-1-yl)-phenyl]-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[4-(4-isobutyryl-piperazin-1-yl)-phenyl]-2-oxo-acetamide,N-{4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-[5-methyl-1-(2-methyl-oxazol-4-ylmethyl)-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-oxazol-2-yl-phenyl)-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-[3-fluoro-4-oxazole-2-yl-phenyl)-2-oxo-acetamide,2-[1-(2-Methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-N-(4-oxazol-2-yl-phenyl)-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(1,2-dimethyl-propyl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(2-methoxy-1-methyl-ethyl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(2-furan-2-yl-1-methyl-ethyl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide,2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-[4-(5-piperidin-1-ylmethyl-oxazol-2-yl)-phenyl]-acetamide,or2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-morpholin-4-yl-phenyl)-2-oxo-acetamide;or a pharmaceutically acceptable salt thereof.